The human genome encodes seven isoforms of importin α which are grouped into three subfamilies known as α1, α2 and α3. All isoforms share a fundamentally conserved architecture that consists of an N-terminal, autoinhibitory, importin-β-binding (IBB) domain and a C-terminal Arm (Armadillo)-core that associates with nuclear localization signal (NLS) cargoes. Despite striking similarity in amino acid sequence and 3D structure, importin-α isoforms display remarkable substrate specificity in vivo. In the present review, we look at key differences among importin-α isoforms and provide a comprehensive inventory of known viral and cellular cargoes that have been shown to associate preferentially with specific isoforms. We illustrate how the diversification of the adaptor importin α into seven isoforms expands the dynamic range and regulatory control of nucleocytoplasmic transport, offering unexpected opportunities for pharmacological intervention. The emerging view of importin α is that of a key signalling molecule, with isoforms that confer preferential nuclear entry and spatiotemporal specificity on viral and cellular cargoes directly linked to human diseases.

INTRODUCTION

Nucleocytoplasmic transport is central to the function of eukaryotic cells and an integral part of the processes that lead to many human diseases. Over the past 30 years, dramatic progress in cell, molecular and structural biology has been instrumental in elucidating the soluble factors mediating the trafficking of cargoes through the nuclear pore complex (NPC), the organization, architecture and assembly of the NPC, and the mechanisms of translocation through it. The overall picture emerging from this large body of work describes nucleocytoplasmic transport as a signal- and energy-mediated process through the large aqueous channel of the NPC, which functions as a semipermeable filter. The importin β-superfamily, named for the founder importin β (also known as karyopherin β1) [1], represents the major class of soluble transport receptors involved in shuttling cargoes through the NPC. Importin β functions as a transport receptor by co-ordinating three biochemical activities: (i) high-affinity binding to a basic nuclear localization signal (NLS) exposed by import cargoes; (ii) avidity for phenylalanine–glycine repeats exposed by several nucleoporins (FG-nups) protruding into the cytoplasm and lining the NPC; and (iii) high-affinity association with Ras-related nuclear protein GTP (RanGTP) which triggers a conformational change to release both NLS-cargoes and FG-nups. Importin β can associate with import cargoes either directly or via adaptors, such as snurportin or importin α [2]. These adaptors can be thought of as specialized cargoes that carry a potent N-terminal NLS, known as the importin β-binding (IBB) domain [3].

Import cargoes expose NLS sequences, exemplified by the monopartite SV40 large T-antigen NLS and the bipartite nucleoplasmin NLS [4], which bind the adapter importin α in the presence of importin β, initiating what is known as the ‘classic’ nuclear import pathway (Figure 1). The heterotrimeric importin β/α/NLS-cargo complex (Figure 2) shuttles through the NPC and delivers the NLS-cargo into the nucleus in a process aided by the small RanGTPase. Although a detailed description of nuclear transport is beyond the scope of the present review, several excellent reviews describing mechanisms governing nucleocytoplasmic transport have been published in recent years [513]. In the present review, we focus on a surprising aspect of the biology of importin α: unlike importin β, which is encoded by a single gene in all eukaryotes, at least seven isoforms of importin α exist in higher eukaryotes. These isoforms display remarkable substrate specificity in vivo, which is not always repeated in vitro. The present review focuses on the biology of importin α isoforms: we take an inventory of known NLS-cargoes specific to importin α isoforms and critically analyse their role in cell physiology and involvement in human diseases.

The classic nuclear import pathway

Figure 1
The classic nuclear import pathway

Importin β, importin α and an NLS-cargo assembly in the cytoplasm travel through the nuclear pore. The disassembly of the import complex is started by the binding of RanGTP to importin β, which causes release of the IBB domain. Disassembly of the NLS-cargo from importin α is a concerted effort of the IBB domain, the nucleoporin Nup50 and the importin α-recycling factor CAS. The empty importins are recycled back to the cytoplasm, where they are released to restart the import cycle via hydrolysis of RanGTP.

Figure 1
The classic nuclear import pathway

Importin β, importin α and an NLS-cargo assembly in the cytoplasm travel through the nuclear pore. The disassembly of the import complex is started by the binding of RanGTP to importin β, which causes release of the IBB domain. Disassembly of the NLS-cargo from importin α is a concerted effort of the IBB domain, the nucleoporin Nup50 and the importin α-recycling factor CAS. The empty importins are recycled back to the cytoplasm, where they are released to restart the import cycle via hydrolysis of RanGTP.

The classic nuclear import complex

Figure 2
The classic nuclear import complex

The diagram is based on the structure of human importin β (beige) bound to the IBB domain (dark blue; PDB 1QGK) and mouse importin α2 (cyan) bound to the nucleoplasmin NLS (grey; PDB 1EJY). The N-terminus and C-terminus of each structure are noted with an ‘N’ or ‘C’, respectively. The illustration was produced using the Chimera program [150].

Figure 2
The classic nuclear import complex

The diagram is based on the structure of human importin β (beige) bound to the IBB domain (dark blue; PDB 1QGK) and mouse importin α2 (cyan) bound to the nucleoplasmin NLS (grey; PDB 1EJY). The N-terminus and C-terminus of each structure are noted with an ‘N’ or ‘C’, respectively. The illustration was produced using the Chimera program [150].

EVOLUTION AND DIVERSIFICATION OF THE IMPORTIN-α GENE IN EUKARYOTES

Functional diversification of the adaptor importin α has occurred throughout the evolution of multicellular animals, paralleling the increasingly complex requirements of higher organisms with their need to perform cell- and tissue-specific functions during development and differentiation [14]. Saccaromyces cerevisiae has a single gene encoding orthologues of importin β and importin α (known as Kap95 and Kap60, respectively). Three importin-α isoforms exist in Drosophila melanogaster and as many as seven isoforms are found in vertebrates (Figure 3). Human importin-α isoforms are well conserved, with 26% identity and 42% conservation in their amino acid sequences, as determined by ClustalW alignment [15] and the BLOSUM62 similarity matrix [16]. They can be divided into three subfamilies: the α1 subfamily containing importin α1 and α8; the α2 subfamily containing importin α3 and α4; and the α3 subfamily, containing importin α5, α6 and α7 (Table 1). A growing number of cellular (Table 2) and viral (Table 3) cargoes rely on specific importin-α isoforms for transport into the nucleus, and important differences in the regulation of these isoforms are just beginning to be understood.

Evolution of importin α

Figure 3
Evolution of importin α

From left to right is a schematic diagram of the evolution of the importin-α gene in Saccharomyces cerevisiae, Drosophila sp. and Homo sapiens; the scale bar represents 0.1 residue changes per amino acid position. Phylogenetic trees for Drosophila and human isoforms were generated with ClustalW [15] and TreeView [151]. The electrostatic surface charge distribution {determined using APBS Tools [152] and PyMol (PyMOL Molecular Graphics System, Version 1.3r1, Schrödinger L. L. C.)} is shown for the isoforms determined crystallographically, namely importin α1 (PDB 4E4 V), importin α3 (PDB 4UAE), importin α5 (PDB 3TJ3), importin α6 (PDB 4U2X) and importin α7 (PDB 4UAD). NS: Not Solved.

Figure 3
Evolution of importin α

From left to right is a schematic diagram of the evolution of the importin-α gene in Saccharomyces cerevisiae, Drosophila sp. and Homo sapiens; the scale bar represents 0.1 residue changes per amino acid position. Phylogenetic trees for Drosophila and human isoforms were generated with ClustalW [15] and TreeView [151]. The electrostatic surface charge distribution {determined using APBS Tools [152] and PyMol (PyMOL Molecular Graphics System, Version 1.3r1, Schrödinger L. L. C.)} is shown for the isoforms determined crystallographically, namely importin α1 (PDB 4E4 V), importin α3 (PDB 4UAE), importin α5 (PDB 3TJ3), importin α6 (PDB 4U2X) and importin α7 (PDB 4UAD). NS: Not Solved.

Table 1
Alternative names of importin-α isoforms
Subfamily Protein names Alternative names Gene name Accession number PDBs 
α1 Importin α1 Karyopherin α2, hSRP1α [17], Rch1 [19], Qip2 [40], NPI-3 [154KPNA2 P52292 4E4 V 
 Importin α8 Karyopherin α7 KPNA7 A9QM74 – 
α2 Importin α3 Karyopherin α4, Qip1 [40KPNA4 O00629 4UAE 
 Importin α4 Karyopherin α3, hSRP1γ [155], Qip2 [156KPNA3 O00505 – 
α3 Importin α5 Karyopherin α1, NPI-1 [45], SRP1 [44], hSRP1 [40KPNA1 P52294 2JDQ, 3TJ3, 4B18 
 Importin α6 Karyopherin α5 KPNA5 O15131 4U2X 
 Importin α7 Karyopherin α6, NPI-2 [157KPNA6 O60684 4UAD 
Subfamily Protein names Alternative names Gene name Accession number PDBs 
α1 Importin α1 Karyopherin α2, hSRP1α [17], Rch1 [19], Qip2 [40], NPI-3 [154KPNA2 P52292 4E4 V 
 Importin α8 Karyopherin α7 KPNA7 A9QM74 – 
α2 Importin α3 Karyopherin α4, Qip1 [40KPNA4 O00629 4UAE 
 Importin α4 Karyopherin α3, hSRP1γ [155], Qip2 [156KPNA3 O00505 – 
α3 Importin α5 Karyopherin α1, NPI-1 [45], SRP1 [44], hSRP1 [40KPNA1 P52294 2JDQ, 3TJ3, 4B18 
 Importin α6 Karyopherin α5 KPNA5 O15131 4U2X 
 Importin α7 Karyopherin α6, NPI-2 [157KPNA6 O60684 4UAD 
Table 2
Selected cellular cargoes specific to importin-α isoforms

Cargoes needed to be either tested with at least two importin-α isoforms or screened with multiple isoforms available, and from these experiments have shown some degree of specificity. Importin-α isoforms: importin α8 was not included because no cargoes specific to it have been identified yet. A blank indicates that an import cargo was not tested for binding to an importin-α isoform, () no interaction, (+) a weak interaction or an interaction that wasn't relevant for nuclear import, and (++) a strong interaction or confirmed preference from a nuclear import assay. Protein source refers to the expression system used to generate importin α (α) and cargo (c): ‘b’=bacteria, ‘e’=eukaryotic and specifically ‘h’=human cells. Only proteins expressed in a eukaryotic expression system carry post-translation modifications.

Experimental methods indicate the assay used to determine physical interactions between an importin-α isoform and a cargo: ‘IP’=immunoprecipitations, ‘PD’=pull downs, ‘DI’=pull downs with purified proteins to ensure physical direct interaction, ‘Y2H’=yeast-two hybrids, ‘MS’=mass spectrometry after IP, ‘IA’=reconstituted import assays in permeabilized cells, ‘SI’=knock down by siRNA, ‘MI’=microinjection, ‘TR’=transfection, ‘DN’=dominant negative importin α5 and ‘KD’=full in vivo knock down.

 Importin-α isoforms Protein source Experimental methods  
Cellular import cargoes α1 α3 α4 α5 α6 α7 α Biochemical Functional Reference 
ADAR2 –  ++ ++   Y2 H – [158
ADAR2R ++  – –   Y2 H – [158
ADAR3 ++  – –   Y2 H – [158
AIRE ++  ++  PD – [159
ARHI (DIRAS3) ++ ++  ++ ++ PD – [129
Arx (NLS1) – ++  ++ – – PD IA, SI [160
BRCA1 ++      Y2 H – [161
BRMS1 – –   ++  Y2 H – [162
Brn2 – –  ++   – IA [55
Cby ++  ++ ++  DI – [163
CIC (mammalian capicua) – – ++ – – – IP, MS – [164
CREB2 (murine) – – – ++  ++ PD – [165
Daxx – ++ – – – – PD – [166
DGKζ – ++  ++   PD – [167
DNA Helicase Q1/RecQL ++ ++    PD, DI IA [39,40
DYRK4 – ++  ++   IP – [168
E47 (transcription factor) ++ ++ – –   – IA [169
Endostatin ++ –  –  – – SI [170
FGF1 ++      – SI [171
GLUT2 ++   –   Y2 H, IP DN [172
GlyR  ++ ++    Y2 H, DI – [173
hnRNP C1/C2 – ++ ++ ++ ++ ++ IP, MS – [174
HuR ++ – – –  – IP, DI – [141
IRF-1 ++      – SI [175
IRF-9 – ++ ++ – – PD – [176
Itk ++   –   Y2 H, IP – [177
JNK1 ++ – –    – IA [178
Keap1 – – – – – ++ PD SI [179
Kir/Gem – – – ++ – – PD, IP SI [180
LSD1 – – ++  ++ PD – [181
Mycd (rat) – –  ++   IP – [182
NBS1 ++ –  –   Y2 H SI [183
NF-κB (p50/p65) – ++ ++ ++ ++ – PD – [43,124
NF-κB (p65) ++ – – – – – – SI [184
NF-κB c-Rel – – – ++ ++ ++ PD – [124
NF-κB p52 – ++ ++ ++ ++ – PD – [124
NF-κB RelB – – – ++ ++ ++ PD – [124
Notch intracellular domain – ++ ++ – – ++ PD SI [185
NUCKS – ++  ++   PD – [186
Oct6 – ++  ++   – IA [55
Orc6 – – – ++  ++ MS – [187
p27 (CDK inhibitor) – ++  ++   DI IA [188
p53 – ++  – – – PD – [189
PABPC – ++   PD, DI – [190
Par3 – – ++ –  – MS – [191
PARP-2 ++    PD – [192
Pin1 – ++ – ++  – IP – [193
PKM2/PIN1 – – – ++  – IP SI [194
RAC3 – ++ – – – – PD, Y2 H – [195
RanBP3 – ++ ++ – – – DI IA [196
RCC1 – ++ ++ – – – DI IA [21,197
RNA helicase A ++ ++ – – – – DI IA [198
Serum response factor – – ++   IP, PD IA [199
SET – ++ – – – IP, DI – [200
pSTAT1 –   ++   IP, PD MI [46
pSTAT1 and pSTAT1/pSTAT2 – –  ++  – PD – [81
pSTAT1 – – – ++ ++ ++ IP – [93
pSTAT1 – – – ++  ++ IP, PD – [201
uSTAT3/pSTAT3 – ++  – ++ – PD SI [202
pSTAT3  ++   PD DN [156
pSTAT3 – – – ++  ++ IP, PD – [201
uSTAT3/pSTAT3 ++  – ++ ++ PD – [129
STAT5 a – ++  – ++ – PD SI [203
STAT6 – ++  – ++ – PD – [204
TBP-2 ++ –  –   Y2 H SI [205
Tpr ++ – – PD SI [206
Wt1 ++ – – –  – PD – [207
XPA – – ++ – – IP SI [208
ZIC3 – –  ++  ++ PD SI [209
Znf131 ++   PD – [210
 Importin-α isoforms Protein source Experimental methods  
Cellular import cargoes α1 α3 α4 α5 α6 α7 α Biochemical Functional Reference 
ADAR2 –  ++ ++   Y2 H – [158
ADAR2R ++  – –   Y2 H – [158
ADAR3 ++  – –   Y2 H – [158
AIRE ++  ++  PD – [159
ARHI (DIRAS3) ++ ++  ++ ++ PD – [129
Arx (NLS1) – ++  ++ – – PD IA, SI [160
BRCA1 ++      Y2 H – [161
BRMS1 – –   ++  Y2 H – [162
Brn2 – –  ++   – IA [55
Cby ++  ++ ++  DI – [163
CIC (mammalian capicua) – – ++ – – – IP, MS – [164
CREB2 (murine) – – – ++  ++ PD – [165
Daxx – ++ – – – – PD – [166
DGKζ – ++  ++   PD – [167
DNA Helicase Q1/RecQL ++ ++    PD, DI IA [39,40
DYRK4 – ++  ++   IP – [168
E47 (transcription factor) ++ ++ – –   – IA [169
Endostatin ++ –  –  – – SI [170
FGF1 ++      – SI [171
GLUT2 ++   –   Y2 H, IP DN [172
GlyR  ++ ++    Y2 H, DI – [173
hnRNP C1/C2 – ++ ++ ++ ++ ++ IP, MS – [174
HuR ++ – – –  – IP, DI – [141
IRF-1 ++      – SI [175
IRF-9 – ++ ++ – – PD – [176
Itk ++   –   Y2 H, IP – [177
JNK1 ++ – –    – IA [178
Keap1 – – – – – ++ PD SI [179
Kir/Gem – – – ++ – – PD, IP SI [180
LSD1 – – ++  ++ PD – [181
Mycd (rat) – –  ++   IP – [182
NBS1 ++ –  –   Y2 H SI [183
NF-κB (p50/p65) – ++ ++ ++ ++ – PD – [43,124
NF-κB (p65) ++ – – – – – – SI [184
NF-κB c-Rel – – – ++ ++ ++ PD – [124
NF-κB p52 – ++ ++ ++ ++ – PD – [124
NF-κB RelB – – – ++ ++ ++ PD – [124
Notch intracellular domain – ++ ++ – – ++ PD SI [185
NUCKS – ++  ++   PD – [186
Oct6 – ++  ++   – IA [55
Orc6 – – – ++  ++ MS – [187
p27 (CDK inhibitor) – ++  ++   DI IA [188
p53 – ++  – – – PD – [189
PABPC – ++   PD, DI – [190
Par3 – – ++ –  – MS – [191
PARP-2 ++    PD – [192
Pin1 – ++ – ++  – IP – [193
PKM2/PIN1 – – – ++  – IP SI [194
RAC3 – ++ – – – – PD, Y2 H – [195
RanBP3 – ++ ++ – – – DI IA [196
RCC1 – ++ ++ – – – DI IA [21,197
RNA helicase A ++ ++ – – – – DI IA [198
Serum response factor – – ++   IP, PD IA [199
SET – ++ – – – IP, DI – [200
pSTAT1 –   ++   IP, PD MI [46
pSTAT1 and pSTAT1/pSTAT2 – –  ++  – PD – [81
pSTAT1 – – – ++ ++ ++ IP – [93
pSTAT1 – – – ++  ++ IP, PD – [201
uSTAT3/pSTAT3 – ++  – ++ – PD SI [202
pSTAT3  ++   PD DN [156
pSTAT3 – – – ++  ++ IP, PD – [201
uSTAT3/pSTAT3 ++  – ++ ++ PD – [129
STAT5 a – ++  – ++ – PD SI [203
STAT6 – ++  – ++ – PD – [204
TBP-2 ++ –  –   Y2 H SI [205
Tpr ++ – – PD SI [206
Wt1 ++ – – –  – PD – [207
XPA – – ++ – – IP SI [208
ZIC3 – –  ++  ++ PD SI [209
Znf131 ++   PD – [210
Table 3
Selected viral cargoes specific to importin-α isoforms

Please refer to the legend to Table 2.

 α Isoforms Protein source Experimental methods  
Viral import cargoes α1 α3 α4 α5 α6 α7 α Biochemical Functional Reference 
Adenoviral E1A ++  – IA [211
Adenoviral E1A ++ ++  ++   IP – [212
BAdV-3 5K2 – ++  –  – PD – [213
Chickunguya virus capsid – ++ – –   PD – [214
Epstein–Barr virus pEBNA-1 – –  ++   DI – [139
Ebola VP24 – – – ++ ++ ++ IP – [93
Haantan virus N ++ ++ – ++   IP – [215
HIV-1 integrase – ++  –  – DI SI [82
HIV-1 integrase ++      DI IA [216
HIV-1 Vpr ++ ++  ++   PD IA [89
HIV-1 Vpr  ++   DI IA [90
Human herpesvirus 6 U69 –   ++ DI IA [217
HPV E1 (bovine) – ++ ++ ++  – DI IA [218
HPV E2 – ++ – ++  – DI – [219
Influenza–NP ++   ++   Y2 H IA [80
Influenza–NP ++  ++  – PD – [81
Influenza–PB2 ++  ++ IP SI [85
Influenza–PB2 – ++   DI – [35
Influenza–PB2 – ++ – – – ++ – SI, KD [63
Nipah virus W – ++ ++ – – – IP – [220
SARS-CoV ORF6 ++ – – –   IP TR [95
SV40 large T antigen ++ – – – – PD – [81
VEE nsP2 – – – ++   IP – [221
 α Isoforms Protein source Experimental methods  
Viral import cargoes α1 α3 α4 α5 α6 α7 α Biochemical Functional Reference 
Adenoviral E1A ++  – IA [211
Adenoviral E1A ++ ++  ++   IP – [212
BAdV-3 5K2 – ++  –  – PD – [213
Chickunguya virus capsid – ++ – –   PD – [214
Epstein–Barr virus pEBNA-1 – –  ++   DI – [139
Ebola VP24 – – – ++ ++ ++ IP – [93
Haantan virus N ++ ++ – ++   IP – [215
HIV-1 integrase – ++  –  – DI SI [82
HIV-1 integrase ++      DI IA [216
HIV-1 Vpr ++ ++  ++   PD IA [89
HIV-1 Vpr  ++   DI IA [90
Human herpesvirus 6 U69 –   ++ DI IA [217
HPV E1 (bovine) – ++ ++ ++  – DI IA [218
HPV E2 – ++ – ++  – DI – [219
Influenza–NP ++   ++   Y2 H IA [80
Influenza–NP ++  ++  – PD – [81
Influenza–PB2 ++  ++ IP SI [85
Influenza–PB2 – ++   DI – [35
Influenza–PB2 – ++ – – – ++ – SI, KD [63
Nipah virus W – ++ ++ – – – IP – [220
SARS-CoV ORF6 ++ – – –   IP TR [95
SV40 large T antigen ++ – – – – PD – [81
VEE nsP2 – – – ++   IP – [221

The importin-α1 subfamily

The α1 subfamily is the least conserved of the importin-α subfamilies, with 55% identity and 71% conservation. Human importin α1 was first discovered almost two decades ago [17] and named hSRP1α based on its similarity to the yeast Kap60, also known as serine-rich protein 1 (SRP1), a suppressor of RNA polymerase 1 [18]. Another of importin α1's alternative names (see Table 1), Rch1 (or Rag cohort 1), originates from one of its first determined binding partners, RAG-1 [19]. At the same time, a similar protein, with 44% of its sequence identical to SRP1 and 76% to human importin α1, was also identified in Xenopus eggs [20]. Since then, importin α1 has been considered to be the general importer of cargoes bearing a classic NLS [21] whereas its mouse homologue, importin α2 (99.2% similar to the human importin α1), has been extensively used for structural studies, both alone [22] and complexed with a variety of different NLS-cargoes [2335]. A second member of the α1 subfamily, importin α8, was recently identified [36], although a homologue had previously been characterized in bovine cells [37]. Due to its recent discovery, little is known about this isoform apart from the fact that it is overexpressed in some forms of prostate cancer [38] and it appears to play a role in development [37].

The importin-α2 subfamily

Both members of the α2 subfamily, importin α3 and α4, were discovered in 1997, soon after importin α1 [3942]. The two isoforms are extremely homologous, with 86% identity and 92% sequence conservation. The isoforms of this family are best known for their specificity for important cargoes such as the transcription factor NF-κB or nuclear factor κ-light-chain-enhancer of activated B cells (p50/p65) [43] and regulator of chromosome condensation (RCC)-1, Ran's only known guanine nucleotide exchange factor [21] (see Table 2). The crystal structure of importin α3 was recently determined when complexed with the influenza A virus polymerase subunit PB2 [35] (see Table 1), whereas the structure of importin α4, arguably very similar to α3, is unknown.

The importin-α3 subfamily

The α3 subfamily has the highest homology to yeast Kap60 and is thought to have branched off earlier in evolution than the other subfamilies [14] (see Figure 3). Importin α5 was discovered about the same time as importin α1, and was initially named NPI-1 based on its interaction with influenza nucleoprotein (NP) [44,45]. Importin α6 [41] and α7 [21] were discovered soon afterwards, but, due to high homology within the family (74% identity and 82% sequence conservation), functional differences between the isoforms have not been determined. However, the most striking difference within this family is the restriction of importin-α6 expression to the testis [41]. The best characterized cargoes specific to this family are the phosphorylated STAT1 (signal transducer and activator of transcription 1) homodimer or STAT1/STAT2 heterodimer [46,47] (see Table 2). These specialized dimeric cargoes contain a non-classic import signal which, unlike classic NLS-cargoes, can import only in the context of STAT1 [48,49] and appears to rely on contacts with the C-terminus of importin α5 [49]. The structure of importin α5 was determined in two different conformations, with influenza A PB2 [50] and the nucleoporin Nup50 [51]; importin α7 was also resolved when complexed with PB2 [35], and a fragment of importin α6 spanning armadillo (Arm) 7–10 was recently found bound to Ebola virus VP24 [52] (see Table 1).

Spatiotemporal distribution of importin-α isoforms

All importin-α isoforms are expressed to some extent in all adult cell types [21,41,53], with the exception of importin α6, which is limited to the testis [41], and importin α8, the expression of which is restricted to the ovaries and early stage embryos [37,54]. However, the relative intracellular concentration of isoforms α1, α3, α4, α5 and α7 has not been accurately determined, and it is not known if any particular isoform is generally abundant. Furthermore, it is increasingly appreciated that the distribution of importin-α isoforms across different cell types and at different developmental stages is important in development and normal cellular functions, e.g. mouse neural differentiation displays a specific expression sequence of importin α: a gradient from high initial importin α1 and low importin α3 and α5, to lower importin α1 and high importin α3 and α5 as differentiation progresses [55]. An additional layer of import regulation in neural differentiation comes from the evidence that certain cargoes such as Oct6 or Brn2 can bind to multiple importin-α isoforms, but their transport outcome varies depending on the isoform. Binding to importin α5 leads to successful nuclear import, whereas binding to importin α1 inhibits cargo import, causing cytoplasmic retention [56]. Notably, these cargoes bind an importin-α1 C-terminal-binding section (iCBS), possibly in a similar fashion to Nup50 [57,58].

The exact mechanism by which importin α1 prevents nuclear import is unknown, but two possible scenarios are either difficulty in complex disassembly or conformational change in the import complex which prevents its import [56]. An examination of importin-α isoform expression in different regions of the mouse brain, at various stages after birth, also shows interesting changes in distribution over time and regions of the brain [59]. Likewise, importin-α isoform expression in spermatogenesis has been extensively studied, showing significant variations in expression levels of importin α1, in particular, throughout the process [58,60,61]. Any one of the importin α4, α5, α7 or α8 knockouts in mice did not lead to abnormal brain development [54,6265], suggesting that the loss of a single isoform gene is probably compensated for in vivo by an isoform of the same subfamily. Instead, the importin α5 and α7 knockouts led to reproductive problems in female mice and the importin α8 knockout causes reduced fertility and sex imbalance in litters due to induced lethality in females [54], suggesting some non-redundant function of these isoforms in reproduction. There have been several recent studies using a proteomic approach to understand cargo specificity in spermatogenesis and development, although they have generally been looking at cargoes only in the context of one or two isoforms rather than the full range [58,66,67].

DISTINCTIVE PROPERTIES OF IMPORTIN-α ISOFORMS

All importin-α isoforms share a fundamentally conserved structure consisting of an N-terminal, autoinhibitory, IBB domain spanning approximately the first 70 residues and a C-terminal helical core containing Armadillo repeats (Arm-core) (see Figure 2). Despite the high sequence similarity, importin-α isoforms present subtle differences in 3D structure and biochemical properties which contribute to their in vivo specificity for specialized import cargoes.

Structure of the Arm-core

The central core of all importin-α isoforms is built by 10 stacked Arm repeats [Figure 4A (i)] and structurally very similar to Kap60 [68]. Secondary structure matching of the four human importin-α isoforms found crystallographically (α1, α3, α5 and α7) (see Table 1) with Kap60 yields an RMSD of between 0.8 and 1.7 Å (1 Å=0.1 nm), underlining a remarkable degree of conservation between the yeast and human proteins. The Arm repeats [Figure 4A (ii)] of importin α are very similar to the HEAT repeats [Figure 4A (iv)] found in importin β; in both proteins, stacks of Arm/HEAT repeats generate superhelical solenoids, which are highly specialized to participate in protein–protein interactions [1,12]. HEAT repeats are composed of two α-helices (named H1 and H2) arranged as a hairpin, which allows for extremely flexible assemblies [69]. In contrast, in Arm repeats the first helix splits into two helices to make a total of three helices (named H1, H2 and H3), which have a triangular arrangement, leading to more rigid assemblies [70,71]. In all importin-α isoforms, two Arm repeats deviate from the standard three-helix architecture: Arm 1, which lacks the first helix (H1) [Figure 4A (iii)] and Arm 5 which has helices H1 and H2 fused together, making it essentially a HEAT repeat [Figure 4A (iv)]. Stacking of Arm repeats generates an extended concave surface, which harbours NLS-binding pockets, and a convex surface. Superimposition of the Arm-core of importin α1, α3, α5 and α7 reveals that the NLS-binding surface is practically identical in all the isoforms [35], whereas the convex surface is quite variable (Figure 4B). This implies that differences in import cargo specificity and binding affinity among importin α isoforms cannot be ascribed to the NLS-binding surface, which is fundamentally identical in all of the a isoforms.

Arm-core structure and conservation

Figure 4
Arm-core structure and conservation

(A) (i) Structure of the Arm-core of importin α3 (PDB 4UAE) with α-helices shown as cylinders. Schematic diagram of (ii) a canonical Arm and (iii) the degenerate Arm 1, missing helix H1 and of (iv) HEAT repeat (equivalent to Arm 5), and (v) Arm 10, which adopts an open conformation in a structure of importin α5 (PDB 2JDQ). (B) Conservation of the NLS-binding surface of importin-α isoforms. Residues identical in all human isoforms were mapped on to a surface representation of importin α1 (PDB 4E4 V). Identical and non-conserved residues are coloured blue and grey, respectively.

Figure 4
Arm-core structure and conservation

(A) (i) Structure of the Arm-core of importin α3 (PDB 4UAE) with α-helices shown as cylinders. Schematic diagram of (ii) a canonical Arm and (iii) the degenerate Arm 1, missing helix H1 and of (iv) HEAT repeat (equivalent to Arm 5), and (v) Arm 10, which adopts an open conformation in a structure of importin α5 (PDB 2JDQ). (B) Conservation of the NLS-binding surface of importin-α isoforms. Residues identical in all human isoforms were mapped on to a surface representation of importin α1 (PDB 4E4 V). Identical and non-conserved residues are coloured blue and grey, respectively.

The Arm-core of importin α has generally been considered to be essentially rigid compared with flexible HEAT-containing proteins such as importin β [71,72]. However, recent molecular dynamic simulations comparing the flexibility of mouse importin α1, and human importins α3 and α7, revealed that importin α3 has a greater range of extension and compression than the other isoforms, potentially due to a hinge at the major NLS-binding site [35]. This flexibility may result in lower binding affinity for classic NLSs at the major NLS-binding pocket and contribute to decreased IBB domain autoinhibition. In direct relation to the flexibility of Arm-core, the initial structure of importin α5, determined when complexed with PB2, had a domain swap of Arm 10's helix H3 between adjacent molecules in the crystal [50], although two subsequent structures found with this isoform show Arm-10 helices neatly stacked (Protein Databank PDBs 3TJ3 and 4B18) [51]. Although the physiological significance of this domain swap is unclear, Arm-10 unfolding in importin α5 may be due to the presence of a bulky Tyr476 at the interface of helices H1 and H2 [Figure 4B (v)]. This residue, which is conserved only in members of the α3 subfamily, but replaced by a glycine in all other isoforms, was proposed to swing inwards between helices H1 and H2, thereby preventing the intramolecular stacking essential to stabilize the folded conformation of Arm 10. Introducing a glycine/alanine at this position in isoforms α5 and α6, as in importin α1, disrupts high-affinity binding to pSTAT1 [49] and Ebola virus VP24 [52], suggesting that an intrinsic flexibility of Arm 10 could be important for binding to non-classic cargoes interacting with the C-terminus of α3-subfamily members.

Autoinhibition by the IBB domain

Similar to Kap60, the murine importin α1 was also found to be autoinhibited by its IBB domain [22]. The latter contains a bipartite basic sequence (‘RRRR(X)17KRR’) and, in the absence of importin β, it folds back to occupy the NLS-binding surface of importin α (Figure 5A). The first basic motif binds at the minor NLS pocket (Arm 6–8) whereas the second basic motif occupies the major NLS-binding box (Arm 2–4) [22,7375]. The intramolecular interaction between IBB domain and Arm-core prevents binding of importin β to an empty importin α, thus representing a regulatory mechanism to prevent futile nuclear translocation of unloaded import complexes. IBB domain autoinhibition is essential in vivo in yeasts, and probably in higher eukaryotes [76], and was initially thought to occur in all human importin-α isoforms. In contrast, recent studies revealed that IBB autoinhibition varies greatly among isoforms and each isoform can be differentially autoinhibited for different NLS-cargoes, e.g. both importin α3 and α5/α7 are significantly less autoinhibited than importin α1 [35]. This is probably explained by subtle differences in the IBB-domain amino acid sequence (Figure 5B): although the major NLS-binding box (‘KRR’) is conserved in all importin-α isoforms, the minor NLS-binding cluster shows significant differences. Importin α1, α5, α6 and α7 all have ‘RRRR’ as their minor NLS-binding box, whereas importin α3/α4 lacks the third arginine (‘RRQR’ and ‘RRHR’, respectively). Furthermore, in α3-subfamily isoforms (α5/α6/α7), the ‘RRRR’ motif is surrounded by an exceptionally acidic patch containing as many as five glutamate/aspartate residues.

Autoinhibition of Arm-core by the IBB domain

Figure 5
Autoinhibition of Arm-core by the IBB domain

(A) Model of the full-length importin α (grey surface) autoinhibited by the IBB domain (blue). The structure shown represents the full-length Kap60 extracted from PDB 1WA5. (B) Alignment of the basic residues of the IBB domain that interact with the major and minor NLS-binding sites of importin α isoforms and Kap60.

Figure 5
Autoinhibition of Arm-core by the IBB domain

(A) Model of the full-length importin α (grey surface) autoinhibited by the IBB domain (blue). The structure shown represents the full-length Kap60 extracted from PDB 1WA5. (B) Alignment of the basic residues of the IBB domain that interact with the major and minor NLS-binding sites of importin α isoforms and Kap60.

The ability to overcome IBB domain autoinhibition also varies greatly among NLS sequences. Monopartite SV40-like NLSs are usually insufficient to overcome IBB autoinhibition and, thus, bind importin-α isoforms exclusively in the presence of importin β. In contrast, recent studies have shown that certain cargoes containing highly basic bipartite or certain non-classic NLSs are able to bind importin-α isoforms efficiently in the absence of importin β; noticeable examples include RCC1 [77], STAT1 [49] and influenza A virus PB2 [35]. In addition, importin α8 presents several variations in the IBB region that make it different from all other isoforms (Figure 5B). In this isoform, which has a predominant nuclear localization, the IBB domain binds with a stronger affinity to importin β and the Arm-core, but shows very weak binding to classic NLS peptides, even in the absence of its IBB domain [36]. Thus, what was once thought to be a universal feature of all isoforms of importin α, autoinhibition, appears to be generally weaker in isoforms of the subfamilies α2 and α3 and strictly cargo dependent.

IMPORTIN-α ISOFORMS IN MODULATION OF HOST–VIRUS INTERACTION

The interaction between importin-α isoforms and viral proteins has been studied since study of the nuclear transport field started, e.g. the prototypical monopartite NLS sequence (P126KKKRRV132), found in hundreds of cellular factors, is derived from the large T antigen of SV40 [78], and the leucine-rich nuclear export signal was first identified in the HIV Rev protein [79]. Intuitively, viruses have proteins that need to enter the nucleus to hijack the host DNA and use the cell's transcriptional machinery. Some viruses have adapted to acquire specificity for certain importin-α isoforms, although the advantage of this specialization is not well understood. Table 3 presents a comprehensive list of all viral proteins known to interact with specific importin-α isoforms. Among them, influenza virus NP was one of the first identified NLS-cargoes to interact with importin α. Subsequent work showed that importin α1 also binds strongly and imports NP, whereas importin α3 associates only weakly with this cargo [80,81]. HIV-1 integrase, on the other hand, relies on only isoform α3 [82] and, in addition, uses a member of the β-karyopherin family, transportin, to gain access to the nucleus [83].

In a more complex example, influenza A virus polymerase subunit PB2, a major virulence determinant implicated in pathogenicity and host adaptation [84], has been shown to have a preference for importin α3 in avian influenza strains. By contrast, in mammalian-adapted strains, PB2 switches dependency to importin α7 [63,85,86], possibly as a result of a limited set of point mutations. Recent work has proposed that the preferential utilization of isoforms α3 and α7 is probably explained by the differential degree of IBB domain autoinhibition for PB2 in these two isoforms, and by the complex structure of the PB2 NLS domain, which contains a bipartite NLS next to a globular domain [35,50]. In vitro binding assays revealed that PB2 efficiently competes with the IBB domain of isoforms α3 and to a lesser extent α7 in the absence of importin β, whereas it is autoinhibited from binding importin α1 [35]. However, PB2 associates with comparable nanomolar affinity to the Arm-core of all isoforms in the absence of the IBB domain [87]. Another important viral protein, HIV-1 Vpr, can also bind to the C-terminal Arm repeats of importin-α isoforms from all three families [88,89], but recent studies have shown a distinct preference for importin α5. Intriguingly, although Vpr binds with similar affinity to all tested isoforms, only importin α5 efficiently released Vpr in the presence of the recycling factor CAS, and, furthermore, silencing CAS inhibited Vpr import [90]. It is unclear why CAS can induce preferential release of Vpr from importin α5, but it suggests a possible additional layer of complexity in the specificity.

In addition to promoting viral genome replication/transcription and virion assembly, another critical viral function is to evade the host's immune response. The JAK (Janus kinase)/STAT pathway is critical in initiating the immune response to viral infections, so, unsurprisingly, it is a target for suppression by many viruses, e.g. both Ebola virus VP24 and hepatitis B polymerase block STAT1 nuclear import by binding to the C-terminus of importin α5, thereby preventing transcription of STAT1-dependent interferon genes [91,92]. VP24 has also been found to bind to other members of the α3 family [93], and a recent structure complexed with importin α6 reveals that it binds to C-terminal Arm 7–10, as opposed to the NLS-binding pockets [52]. VP24 association with importin α5 does not prevent a classic NLS-cargo from binding, suggesting that VP24 specifically blocks STAT1 import rather than all importin-α5-mediated import. However, it was also found that VP24 forms oligomers that bind to the plasma membrane [94], which could effectively sequester importin α5 in the cytoplasm and prevent any cargo relying on the α3 family shuttling through the NPC. Severe acute respiratory syndrome coronavirus (SARS-CoV) ORF6 also blocks STAT1 signalling by an indirect mechanism, via the sequestration of importin α1 on the surface of the endoplasmic reticulum [95]. Although importin α1 as such does not import STAT1, it has been hypothesized that loss of α1 increases competition for importin-α5 binding, thereby reducing the net influx of STAT1 into the nucleus. A follow-up paper from the same group identified additional transcription factors, the transcription of which was disrupted by the ORF6 sequestration of importin α1, and some of these factors, such as cAMP response element-binding protein 1 (CREB1), SMAD4, p53 and Oct3/4, are important in the response to viral infection [96]. In addition to targeting importin α, the non-classic NLS of STAT1 is itself a target for reducing the antiviral response. A well-known example is the vaccinia virus protein VH1 [97], which dephosphorylates Tyr701 of STAT1 [98,99], thereby causing a conformational change that prevents exposure of STAT1's non-classic NLS to importin α5 [49], and blocks nuclear import and transcription of interferon genes.

INVOLVEMENT OF IMPORTIN-α ISOFORMS IN HUMAN DISEASES

Importin α isoforms in cancer

Importin-α isoform expression is altered in many forms of cancer. In most cases, the up-regulation of the KPNA2 gene (encoding importin α1, see Table 1) indicates a poor prognosis, making it a useful biomarker in breast [100], ovarian [101], cervical [102], prostate [103] and bladder [104] cancer, melanoma [105], squamous cell carcinoma [106], hepatocellular carcinoma [107], lung cancer [108], astrocytic glioma [109] and anaplastic oligoastrocytoma [110]. In some cases, knock down of importin α1 with siRNA could reduce the proliferation of cancerous cells [103,108], but in others it had no effect [102]. Of particular interest was a xenograft study of epithelial ovarian carcinoma in mice, in which transplanted tumours either had KPNA2 knocked down with siRNA, or additionally induced. It was found that knockdown of KPNA2 reduced tumour volume, whereas increased expression of KPNA2 increased tumour volume [111]. Other nucleocytoplasmic transporters, such as importin β [102] and CRM1 [102,110], are also found to be up-regulated in some cancers. One proposed mechanism for this up-regulation is the deregulated activity of the E2F transcription factor, which can up-regulate both KPNA2 and the importin-β gene [112]. E2F is itself regulated by the retinoblastoma protein (Rb) pathway, which is frequently disrupted in cancer. Another importin-α isoform found to have irregular expression in cancerous cells is importin α8. Normally expressed only in oocytes and early embryos, irregular expression of importin α8 in several pancreatic cancer cell lines contributes significantly to the proliferation of these cells [38].

Importin-α isoforms in the nervous system

Specific importin-α isoforms play a role in both normal and abnormal brain and neuron function (reviewed by Perry and Fainzilber [113]). Importin α has been identified as critical in the neurons' ability to start a regenerative response in injured nerve. Importin α and β form a high-affinity complex with STAT3 that traffics retrogradely with the motor protein dynein from the axon back to the nucleus [114]. In an interesting variation on its role as a karyopherin, importin α5 was found to be critical as an adaptor to microtubules. Knock down of importin α5 in injured neurons blocked STAT3 signalling after injury, but direct injection of STAT3 into the axonal bodies, where it can be imported by other importin-α isoforms, could rescue STAT3 signalling [115], suggesting a unique role for importin α5 as a multifunctional transporter. Specific importin-α isoform expression has also been implicated in neuronal differentiation and development [55]. Analysis of the expression of importin-α isoforms in different regions of the mouse brain between birth and adulthood shows a distinct shift in levels and ratios of importin-α isoform expression [59]. A mutation in human importin α8 has also been found to be associated with improper neuronal development [116]. However, the redundancy of the importin-α isoforms still allows for proper brain development even when one of these isoforms is lost, as seen when importin α5 was knocked down in mice [62].

Importin-α isoforms can also play a role in diseased states of the brain, e.g. in schizophrenia, importin-α3 expression is decreased, resulting in reduced NF-κB signalling. This loss of expression is associated with a single nucleotide polymorphism (SNP) in the KPNA4 gene (encoding importin α3), which is also a marker for increased susceptibility to schizophrenia [117]. In addition, certain SNPs of the KPNA3 gene (encoding importin α4) have been correlated with susceptibility to schizophrenia in some populations [118,119]. Importin α1 is also misregulated in Alzheimer's disease, due to it sequestration in the Hirano bodies of hippocampal neurons. The cause of this sequestration is unclear, but its result is a distinct mislocalization of critical NLS-cargoes, such as p27 [120].

Importin-α isoforms in the heart

Recent studies have shown a loss of importin-α expression in ageing myocardial tissues. In myocardial endothelial cells, a reduction in the levels of both importin α1 and importin α3 mRNA and protein was associated with reduced import of hypoxia-inducible factor 1α, which regulates vascular endothelial growth factor expression, a key component in angiogenesis. Thus, loss of importin-α expression in ageing myocardial cells could make recovery after heart disease more difficult for elderly patients [121]. In a study of human fibroblasts, the expression of importin α1 decreased steadily from children to adults to elderly people, whereas importin-β expression over this range was consistent [122]. In addition to loss of importin α1 in ageing myocardial cells, the microRNA miR-181b is able to reduce the signalling of NF-κB in the vascular endothelium by knocking down importin α3 expression [123]. The classic NF-κB p50/p65 heterodimer was first identified as specific to importin α3 and α4 [43], but subsequent studies have shown that it can also bind to members of the α3 family, depending on the expression system, implicating post-translational modifications [124]. This is corroborated by the observation that loss of importin α3 in the vascular endothelium blocks NF-κB signalling, but is compensated for by importin α5 in leukocytes [125].

Other pathologies

The nucleocytoplasmic shuttling of NF-κB also plays a key role in inflammatory bowel disease (IBD). Prohibitin (PHB) 1 is found to be down-regulated during IBD by tumour necrosis factor α (TNF-α), along with increased NF-κB signalling. However, when expression of PHB is restored, NF-κB signalling is reduced. Theiss et al [126] determined that expression of PHB caused suppression of importin α3 and α4, thus preventing the nuclear import of NF-κB despite cell stimulation; however, the mechanism for this suppression is unknown. Similarly, NF-κB and STAT3 signalling are found to be increased in nephropathy due to the down-regulation of miR-223, which causes increased expression of importin α4 and α5 [127].

REGULATION OF IMPORTIN-α ISOFORMS

An attentive review of the literature suggests at least four distinct strategies by which the availability of importin-α isoforms is controlled and regulated in response to endogenous and viral effectors (illustrated in Figure 6).

Cellular strategies of regulating importin-α isoforms

Figure 6
Cellular strategies of regulating importin-α isoforms

Schematic diagrams of: (A) microRNA-mediated regulation of importin-α expression; (B) regulation of import by sequestration of importin α; (C) regulation of import by degradation of importin α; and (D) regulation of import by post-translational modifications of importin α.

Figure 6
Cellular strategies of regulating importin-α isoforms

Schematic diagrams of: (A) microRNA-mediated regulation of importin-α expression; (B) regulation of import by sequestration of importin α; (C) regulation of import by degradation of importin α; and (D) regulation of import by post-translational modifications of importin α.

Transcriptional regulation by microRNAs

The pool of importin-α isoforms can be reduced at the transcriptional level by microRNA-mediated degradation of importin-α isoform mRNAs. Glinsky et al [128] predicted that importin α, and importin α5 in particular, is a major microRNA target in a variety of human diseases. This prediction was corroborated by subsequent studies with miR-181b, which was found to specifically down-regulate importin-α3 expression, thereby blocking NF-κB import and signalling in epithelial cells (Figure 6A) [123,125]. A microRNA not included in the Glinsky analysis, miR-223, was found to block expression of importin α4 and α5; accordingly, decreased expression of miR-223 in nephropathy led to increased signalling of NF-κB and STAT1, possibly by expression of isoforms α4 and α5, respectively [127].

Regulation of importin-α isoform availability by sequestration

Importin-α availability can be altered post-translationally by sequestration. As previously described, Ebola VP24 binds the C-terminus of the α3-subfamily isoforms, competing for binding with STAT1 and thereby blocking its import (Figure 6B). An endogenous factor that uses a similar strategy is ARHI, a Ras homologue, which acts as a tumour suppressor and the expression of which is lost in many breast and ovarian cancers. ARHI binds several isoforms of importin α–α1, α3, α6 and α7, but not α5–and, by doing so, it blocks import of phosphorylated STAT3 (pSTAT3) and classic NLS-cargoes [129].

Regulation of importin-α isoform concentration by targeted degradation

Another approach to reducing nucleocytoplasmic transport of expressed importin-α isoforms is targeted degradation. The porcine reproductive and respiratory syndrome virus (PRRSV) (see Table 2) can inhibit the interferon response by targeted proteasome-mediated degradation of pig importin α5. PRRSV protein Nsp1β mediates this degradation by causing an increase in ubiquitination of importin α5, although the mechanism for this is unknown [130]. Similar behaviour is seen from the foot-and-mouth-disease virus protein 3Cpro (see Table 2), which has protease activity and directly degrades importin α5 [131]. There are also endogenous approaches to targeted degradation of importin α, implemented as a response to viral infection or during cell death. Natural killer cells of the immune system are able to fight viral replication by inducing apoptosis in target cells through release of a variety of proteolytic enzymes. Among these is granzyme K, which has been found to be of particular importance as a response to influenza infection [132]. Granzyme K is a tryptase and can cleave both importin α and importin β so that they cannot bind to each other, thus blocking cargo import (Figure 6C). Interestingly, it was observed that granzyme K could cleave all human importin α isoforms at a location upstream of the IBB, at a conserved arginine residue critical for binding to importin β. This degradation has the effect of blocking viral replication by preventing the nuclear import of key influenza proteins such as NP and PB2 [133]. Importin-α cleavage has also been found to play a role in apoptosis, when various caspases are capable of cleaving the IBB domain from importin α1, α3, α4, and α5. ΔIBB importin α could still accumulate in the nucleus, a behaviour seen previously for ΔIBB importin α from all families [134], and was found to block DNA replication by sequestering the DNA replication licensing factor (MCM) [135]. Finally, importin α5 was recently found to be a substrate for the ubiquitin ligase activity of RAG-1, perhaps as a method of regulation of RAG-1 activity [136]. RAG-1, best known for its role in V(D)J recombination, is also active as a ubiquitin ligase. Interestingly, although RAG-1 is imported into the nucleus by importin α1, not importin α5, it binds to importin α5 weakly outside its functional NLS [137].

Regulation of importin-α isoforms activity by post-translational modification

Post-translational modification of importin α and NLS-cargoes can both up- and down-regulate nuclear imports [138]. One excellent importin-α isoform-specific example is the phosphorylation of Epstein–Barr virus nuclear antigen 1 (EBNA-1). Although the unphosphorylated NLS is sufficient for nuclear import, it binds to its specific adaptor importin α5 with low affinity. Phosphorylation of the NLS accelerates the rate of import and also significantly increases binding to importin α5 [49,139]. Phosphorylation and acetylation of the importin α receptor itself have also been observed. Bannister et al. [140] found that the acetylation of importin α1 by CBP/p300 at Lys22, upstream of the NLS, enhances association with importin β. CBP/p300 was also able to acetylate importin α7 but not importin α3. These authors identified a ‘GK’ motif as essential for acetylation of this importin α1, though they did not test for this in importin α7 [140]. Wang et al. [141] found that 5′-AMP-activated protein kinase (AMPK) is an upstream regulator of CBP/p300, thereby inducing importin-α acetylation and, in addition, that AMPK itself could also phosphorylate importin α1 at Ser105. The combination of these two modifications significantly up-regulates human antigen R (HuR) nuclear import, whereas transfection with importin-α1 mutants lacking either modification site caused no increase in import. Acetylation at Lys22 is predicted to increase the affinity of the IBB domain for importin β, whereas phosphorylation of Ser105 is predicted to increase affinity for an NLS at the major NLS-binding pocket (Figure 6D) [141]. It is interesting to note that importin α7 has a ‘GK’ motif several residues upstream of where it is found in importin α1 (Lys9 compared with Lys22), so it is unclear if acetylation of this isoform would have the same effect as acetylation of importin α1. Importin α3, which is not acetylated, has no ‘GK’ motif in the IBB domain. In addition, no other isoform has a serine near the equivalent of importin α1's residue 105.

CONCLUSIONS AND PERSPECTIVES

It has been 20 years since the discovery of human importin α1 [17], during which time a total of 7 isoforms and over 75 isoform-specific import cargoes have been identified (see Tables 2 and 3). As of September 2014, a Medline search for ‘importin α’ and ‘isoform’ identified 150 publications, signifying an explosion in the number of pathways recognized as mediated by specific importin-α isoforms. As described in the present review, importin-α isoforms play a pivotal role in the nuclear import of critically important transcription factors such as STATs and NF-κB, recently identified as targets of importin α5 and importin α3, respectively. A precise display of importin-α isoform expression also seems to be critical during development, particularly of the brain. Misregulation of specific importin-α isoform expression, availability and activity occurs in disease states in response to pathogens and in cancer, which prompted many to use importin α1 as a biomarker. Thus, apart from the classic role as ‘karyopherins’, importin-α isoforms play a pleiotropic role as signalling molecules in cell physiology, development and human diseases.

The dilemma of in vivo specificity

What makes importin-α isoforms specific in vivo? On the basis of the literature reviewed here, we identify three factors that may help answer this question. First, in the simplest possible scenario, cell type availability of different isoforms could dictate specificity for certain import cargoes. The intracellular concentration of different isoforms has not been accurately determined, leaving open the possibility that the first discovered isoform, importin α1, may not necessarily be the most abundant in all cell types. Furthermore, as previously described, there are several mechanisms to up- or down-regulate the relative concentration of specific importin-α isoforms (i.e. microRNAs, sequestration, degradation and post-translational modifications), thereby generating fluctuations in the intracellular concentration of importin-α isoforms which may lead to a preferential association with certain import cargos. Secondly, not all ‘import cargoes are created equal’ in a cell. In addition to the NLS, other binding determinants in an import cargo can provide preferential affinity, and hence specificity, to an importin-α isoform. Good examples of this are non-classic cargoes such as STAT1 [49] and VP24 [52] which strongly bind the C-terminus of importin α, outside the minor NLS-binding pocket. Alternatively, certain NLS-cargoes such as RCC1 [77] and PB2 [35] have NLSs flanked by a folded domain that contributes additional binding determinants for importin α3. Finally, not all importin-α isoforms are equally autoinhibited by their IBB domains, suggesting that different levels of intramolecular autoinhibition may determine preferences in association (and hence specificity) of an isoform for a given import cargo. Similarly the disassembly of an import cargo from an importin-α isoform can potentially dictate isoform specificity, as in the case of Vpr. This small HIV-1-encoded protein binds to several importin-α isoforms (see Table 3), but is specific for importin α5 due to its inability to be removed from the other isoforms by CAS [90]. In all the strategies described above, post-translational modifications in both import cargoes and importin α can modulate the affinity and hence specificity of a given isoform for an import cargo [142].

Targeted inhibition of specific importin-α isoforms

A goal of this field is to develop selective inhibitors that block specific isoforms (or similar isoforms within a subfamily) without affecting the bulk of NLS-cargoes moving through the NPC. There are already examples of peptides designed to target importin α that block the classic nuclear import, such as cSN50.1, Bimax2 and ivermectin. Of these, only cSN50.1 has been shown to have importin-α isoform specificity. It is a peptide based on the NLS of the NF-κB subunit p50 [143], shown to bind with nanomolar affinity to importin α5 and only very weakly to other isoforms [144]. This peptide has been shown to block import of NF-κB along with a variety of other key transcription factors, thereby suppressing proinflammatory signals [145,146]. Bimax2, designed by Kosugi et al. [147], is a monopartite NLS that acts as a high-affinity general inhibitor of the classic nuclear import pathway. Ivermectin is a small molecule commonly used as an anti-parasitic drug, which, it has recently been determined, blocks cargo binding to importin α [148,149]. In summary, the work done to date to understand the regulation of importin-α isoform expression is just the tip of the iceberg; a thorough analysis of importin-α isoform expression, in vivo interactions and post-translational regulation will allow better understanding of their role in cell physiology. Due to their function as gatekeepers to the nucleus and unique specialization for important signalling cargoes often associated with human disease, importin-α isoforms are excellent targets for the development of new pharmacological agents.

FUNDING

This work was supported in part by a National Institutes of Health (NIH) grant (GM074846) to G.C.R.A.P. was supported by an NIH award (T32 GM100836) from the National Institute of General Medical Sciences.

Abbreviations

     
  • AMPK

    5′-AMP-activated protein kinase

  •  
  • Arm

    armadillo

  •  
  • IBB

    importin-β-binding

  •  
  • IBD

    inflammatory bowel disease

  •  
  • NF-κB

    nuclear factor κ-light-chain-enhancer of activated B cells

  •  
  • NLS

    nuclear localization signal

  •  
  • NP

    nucleoprotein

  •  
  • NPC

    nuclear pore complex

  •  
  • nup/Nup

    nucleoporin

  •  
  • PHB

    prohibitin

  •  
  • PRRSV

    porcine reproductive and respiratory syndrome virus

  •  
  • Ran

    Ras-related nuclear protein

  •  
  • RCC

    regulator of chromosome condensation

  •  
  • Rch1

    Rag cohort 1

  •  
  • SNP

    single nucleotide polymorphism

  •  
  • SRP1

    serine-rich protein 1

  •  
  • STAT

    signal transducer and activator of transcription

References

References
1
Cingolani
G.
Petosa
C.
Weis
K.
Muller
C.W.
Structure of importin-beta bound to the IBB domain of importin-alpha
Nature
1999
, vol. 
399
 (pg. 
221
-
229
)
[PubMed]
2
Goldfarb
D.S.
Corbett
A.H.
Mason
D.A.
Harreman
M.T.
Adam
S.A.
Importin alpha: a multipurpose nuclear-transport receptor
Trends Cell Biol.
2004
, vol. 
14
 (pg. 
505
-
514
)
[PubMed]
3
Lott
K.
Cingolani
G.
The importin beta binding domain as a master regulator of nucleocytoplasmic transport
Biochim. Biophys. Acta
2011
, vol. 
1813
 (pg. 
1578
-
1592
)
[PubMed]
4
Jans
D.A.
Xiao
C.Y.
Lam
M.H.
Nuclear targeting signal recognition: a key control point in nuclear transport?
Bioessays
2000
, vol. 
22
 (pg. 
532
-
544
)
[PubMed]
5
Gorlich
D.
Kutay
U.
Transport between the cell nucleus and the cytoplasm
Annu. Rev. Cell Dev. Biol.
1999
, vol. 
15
 (pg. 
607
-
660
)
[PubMed]
6
Macara
I.G.
Transport into and out of the nucleus
Microbiol. Mol. Biol. Rev.
2001
, vol. 
65
 (pg. 
570
-
594
)
[PubMed]
7
Bednenko
J.
Cingolani
G.
Gerace
L.
Nucleocytoplasmic transport: navigating the channel
Traffic
2003
, vol. 
4
 (pg. 
127
-
135
)
[PubMed]
8
Fahrenkrog
B.
Aebi
U.
The nuclear pore complex: nucleocytoplasmic transport and beyond
Nat. Rev. Mol. Cell Biol.
2003
, vol. 
4
 (pg. 
757
-
766
)
[PubMed]
9
Weis
K.
Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle
Cell
2003
, vol. 
112
 (pg. 
441
-
451
)
[PubMed]
10
Poon
I.K.
Jans
D.A.
Regulation of nuclear transport: central role in development and transformation?
Traffic
2005
, vol. 
6
 (pg. 
173
-
186
)
[PubMed]
11
Stewart
M.
Molecular mechanism of the nuclear protein import cycle
Nat. Rev. Mol. Cell Biol.
2007
, vol. 
8
 (pg. 
195
-
208
)
[PubMed]
12
Cook
A.
Bono
F.
Jinek
M.
Conti
E.
Structural biology of nucleocytoplasmic transport
Annu. Rev. Biochem.
2007
, vol. 
76
 (pg. 
647
-
671
)
[PubMed]
13
Wente
S.R.
Rout
M.P.
The nuclear pore complex and nuclear transport
Cold Spring Harb. Perspect. Biol.
2010
, vol. 
2
 pg. 
a000562
 
[PubMed]
14
Mason
D.A.
Stage
D.E.
Goldfarb
D.S.
Evolution of the metazoan-specific importin alpha gene family
J. Mol. Evol.
2009
, vol. 
68
 (pg. 
351
-
365
)
[PubMed]
15
Larkin
M.A.
Blackshields
G.
Brown
N.P.
Chenna
R.
McGettigan
P.A.
McWilliam
H.
Valentin
F.
Wallace
I.M.
Wilm
A.
Lopez
R.
, et al. 
Clustal W and Clustal X version 2.0
Bioinformatics
2007
, vol. 
23
 (pg. 
2947
-
2948
)
[PubMed]
16
Henikoff
S.
Henikoff
J.G.
Amino acid substitution matrices from protein blocks
Proc. Natl. Acad. Sci. U. S. A.
1992
, vol. 
89
 (pg. 
10915
-
10919
)
[PubMed]
17
Weis
K.
Mattaj
I.W.
Lamond
A.I.
Identification of hSRP1 alpha as a functional receptor for nuclear localization sequences
Science
1995
, vol. 
268
 (pg. 
1049
-
1053
)
[PubMed]
18
Yano
R.
Oakes
M.
Yamaghishi
M.
Dodd
J.A.
Nomura
M.
Cloning and characterization of SRP1, a suppressor of temperature-sensitive RNA polymerase I mutations, in Saccharomyces cerevisiae
Mol. Cell. Biol.
1992
, vol. 
12
 (pg. 
5640
-
5651
)
[PubMed]
19
Cuomo
C.A.
Kirch
S.A.
Gyuris
J.
Brent
R.
Oettinger
M.A.
Rch1, a protein that specifically interacts with the RAG-1 recombination-activating protein
Proc. Natl. Acad. Sci. USA.
1994
, vol. 
91
 (pg. 
6156
-
6160
)
20
Gorlich
D.
Prehn
S.
Laskey
R.A.
Hartmann
E.
Isolation of a protein that is essential for the first step of nuclear protein import
Cell.
1994
, vol. 
79
 (pg. 
767
-
778
)
[PubMed]
21
Kohler
M.
Speck
C.
Christiansen
M.
Bischoff
F.R.
Prehn
S.
Haller
H.
Gorlich
D.
Hartmann
E.
Evidence for distinct substrate specificities of importin alpha family members in nuclear protein import
Mol. Cell. Biol.
1999
, vol. 
19
 (pg. 
7782
-
7791
)
[PubMed]
22
Kobe
B.
Autoinhibition by an internal nuclear localization signal revealed by the crystal structure of mammalian importin alpha
Nat. Struct. Biol.
1999
, vol. 
6
 (pg. 
388
-
397
)
[PubMed]
23
Fontes
M.R.
Teh
T.
Kobe
B.
Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-alpha
J. Mol. Biol.
2000
, vol. 
297
 (pg. 
1183
-
1194
)
[PubMed]
24
Fontes
M.R.
Teh
T.
Jans
D.
Brinkworth
R.I.
Kobe
B.
Structural basis for the specificity of bipartite nuclear localization sequence binding by importin-alpha
J. Biol. Chem.
2003
, vol. 
278
 (pg. 
27981
-
27987
)
[PubMed]
25
Yang
S.N.
Takeda
A.A.
Fontes
M.R.
Harris
J.M.
Jans
D.A.
Kobe
B.
Probing the specificity of binding to the major nuclear localization sequence-binding site of importin-alpha using oriented peptide library screening
J. Biol. Chem.
2010
, vol. 
285
 (pg. 
19935
-
19946
)
[PubMed]
26
Giesecke
A.
Stewart
M.
Novel binding of the mitotic regulator TPX2 (target protein for Xenopus kinesin-like protein 2) to importin-alpha
J. Biol. Chem.
2011
, vol. 
285
 (pg. 
17628
-
17635
)
27
Takeda
A.A.
de Barros
A.C.
Chang
C.W.
Kobe
B.
Fontes
M.R.
Structural basis of importin-alpha-mediated nuclear transport for Ku70 and Ku80
J. Mol. Biol.
2011
, vol. 
412
 (pg. 
226
-
234
)
[PubMed]
28
de Barros
A.C.
Takeda
A.A.
Chang
C.W.
Kobe
B.
Fontes
M.R.
Structural basis of nuclear import of flap endonuclease 1 (FEN1)
Acta Crystallogr. D Biol. Crystallogr.
2012
, vol. 
68
 (pg. 
743
-
750
)
[PubMed]
29
Marfori
M.
Lonhienne
T.G.
Forwood
J.K.
Kobe
B.
Structural basis of high-affinity nuclear localization signal interactions with importin-alpha
Traffic
2012
, vol. 
13
 (pg. 
532
-
548
)
[PubMed]
30
Chang
C.W.
Counago
R.M.
Williams
S.J.
Boden
M.
Kobe
B.
Distinctive conformation of minor site-specific nuclear localization signals bound to importin-alpha
Traffic
2013
, vol. 
14
 (pg. 
1144
-
1154
)
[PubMed]
31
Roman
N.
Christie
M.
Swarbrick
C.M.
Kobe
B.
Forwood
J.K.
Structural characterisation of the nuclear import receptor importin alpha in complex with the bipartite NLS of Prp20
PLoS ONE
2013
, vol. 
8
 pg. 
e82038
 
[PubMed]
32
Rona
G.
Marfori
M.
Borsos
M.
Scheer
I.
Takacs
E.
Toth
J.
Babos
F.
Magyar
A.
Erdei
A.
Bozoky
Z.
, et al. 
Phosphorylation adjacent to the nuclear localization signal of human dUTPase abolishes nuclear import: structural and mechanistic insights
Acta Crystallogr. D Biol. Crystallogr.
2013
, vol. 
69
 (pg. 
2495
-
2505
)
[PubMed]
33
Chen
M.H.
Ben-Efraim
I.
Mitrousis
G.
Walker-Kopp
N.
Sims
P.J.
Cingolani
G.
Phospholipid scramblase 1 contains a nonclassical nuclear localization signal with unique binding site in importin alpha
J. Biol. Chem.
2005
, vol. 
280
 (pg. 
10599
-
10606
)
[PubMed]
34
Lott
K.
Bhardwaj
A.
Sims
P.J.
Cingolani
G.
A minimal nuclear localization signal (NLS) in human phospholipid scramblase 4 that binds only the minor NLS-binding site of importin alpha1
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
28160
-
28169
)
[PubMed]
35
Pumroy
R.A.
Ke
S.
Hart
D.J.
Zachariae
U.
Cingolani
G.
Molecular determinants for nuclear import of influenza A PB2 by importin α isoforms 3 and 7
Structure
2014
 
doi: 10.1016/j.str.2014.11.015
36
Kelley
J.B.
Talley
A.M.
Spencer
A.
Gioeli
D.
Paschal
B.M.
Karyopherin alpha7 (KPNA7), a divergent member of the importin alpha family of nuclear import receptors
BMC Cell Biol.
2010
, vol. 
11
 pg. 
63
 
37
Tejomurtula
J.
Lee
K.B.
Tripurani
S.K.
Smith
G.W.
Yao
J.
Role of importin alpha8, a new member of the importin alpha family of nuclear transport proteins, in early embryonic development in cattle
Biol. Reprod.
2009
, vol. 
81
 (pg. 
333
-
342
)
[PubMed]
38
Laurila
E.
Vuorinen
E.
Savinainen
K.
Rauhala
H.
Kallioniemi
A.
KPNA7, a nuclear transport receptor, promotes malignant properties of pancreatic cancer cells in vitro
Exp. Cell Res.
2014
, vol. 
322
 (pg. 
159
-
167
)
[PubMed]
39
Miyamoto
Y.
Imamoto
N.
Sekimoto
T.
Tachibana
T.
Seki
T.
Tada
S.
Enomoto
T.
Yoneda
Y.
Differential modes of nuclear localization signal (NLS) recognition by three distinct classes of NLS receptors
J. Biol. Chem.
1997
, vol. 
272
 (pg. 
26375
-
26381
)
[PubMed]
40
Seki
T.
Tada
S.
Katada
T.
Enomoto
T.
Cloning of a cDNA encoding a novel importin-alpha homologue, Qip1: discrimination of Qip1 and Rch1 from hSrp1 by their ability to interact with DNA helicase Q1/RecQL
Biochem. Biophys. Res. Commun.
1997
, vol. 
234
 (pg. 
48
-
53
)
[PubMed]
41
Kohler
M.
Ansieau
S.
Prehn
S.
Leutz
A.
Haller
H.
Hartmann
E.
Cloning of two novel human importin-alpha subunits and analysis of the expression pattern of the importin-alpha protein family
FEBS Lett.
1997
, vol. 
417
 (pg. 
104
-
108
)
[PubMed]
42
Takeda
S.
Fujiwara
T.
Shimizu
F.
Kawai
A.
Shinomiya
K.
Okuno
S.
Ozaki
K.
Katagiri
T.
Shimada
Y.
Nagata
M.
, et al. 
Isolation and mapping of karyopherin alpha 3 (KPNA3), a human gene that is highly homologous to genes encoding Xenopus importin, yeast SRP1 and human RCH1
Cytogenet. Cell Genet.
1997
, vol. 
76
 (pg. 
87
-
93
)
[PubMed]
43
Fagerlund
R.
Kinnunen
L.
Kohler
M.
Julkunen
I.
Melen
K.
NF-{kappa}B is transported into the nucleus by importin {alpha}3 and importin {alpha}4
J. Biol. Chem.
2005
, vol. 
280
 (pg. 
15942
-
15951
)
[PubMed]
44
Cortes
P.
Ye
Z.S.
Baltimore
D.
RAG-1 interacts with the repeated amino acid motif of the human homologue of the yeast protein SRP1
Proc. Natl. Acad. Sci. U. S. A.
1994
, vol. 
91
 (pg. 
7633
-
7637
)
[PubMed]
45
O'Neill
R.E.
Palese
P.
NPI-1, the human homolog of SRP-1, interacts with influenza virus nucleoprotein
Virology
1995
, vol. 
206
 (pg. 
116
-
125
)
[PubMed]
46
Sekimoto
T.
Imamoto
N.
Nakajima
K.
Hirano
T.
Yoneda
Y.
Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation with NPI-1, but not Rch1
EMBO J.
1997
, vol. 
16
 (pg. 
7067
-
7077
)
[PubMed]
47
Fagerlund
R.
Melen
K.
Kinnunen
L.
Julkunen
I.
Arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5
J. Biol. Chem.
2002
, vol. 
277
 (pg. 
30072
-
30078
)
[PubMed]
48
Meyer
T.
Begitt
A.
Lodige
I.
van Rossum
M.
Vinkemeier
U.
Constitutive and IFN-gamma-induced nuclear import of STAT1 proceed through independent pathways
EMBO J.
2002
, vol. 
21
 (pg. 
344
-
354
)
[PubMed]
49
Nardozzi
J.
Wenta
N.
Yasuhara
N.
Vinkemeier
U.
Cingolani
G.
Molecular basis for the recognition of phosphorylated STAT1 by importin alpha5
J. Mol. Biol.
2010
, vol. 
402
 (pg. 
83
-
100
)
[PubMed]
50
Tarendeau
F.
Boudet
J.
Guilligay
D.
Mas
P.J.
Bougault
C.M.
Boulo
S.
Baudin
F.
Ruigrok
R.W.
Daigle
N.
Ellenberg
J.
, et al. 
Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit
Nat. Struct. Mol. Biol.
2007
, vol. 
14
 (pg. 
229
-
233
)
[PubMed]
51
Pumroy
R.A.
Nardozzi
J.D.
Hart
D.J.
Root
M.J.
Cingolani
G.
Nucleoporin Nup50 stabilizes closed conformation of armadillo repeat 10 in importin alpha5
J. Biol. Chem.
2012
, vol. 
287
 (pg. 
2022
-
2031
)
[PubMed]
52
Xu
W.
Edwards
M.R.
Borek
D.M.
Feagins
A.R.
Mittal
A.
Alinger
J.B.
Berry
K.N.
Yen
B.
Hamilton
J.
Brett
T.J.
, et al. 
Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1
Cell Host Microbe
2014
, vol. 
16
 (pg. 
187
-
200
)
[PubMed]
53
Tsuji
L.
Takumi
T.
Imamoto
N.
Yoneda
Y.
Identification of novel homologues of mouse importin alpha, the alpha subunit of the nuclear pore-targeting complex, and their tissue-specific expression
FEBS Lett.
1997
, vol. 
416
 (pg. 
30
-
34
)
[PubMed]
54
Hu
J.
Wang
F.
Yuan
Y.
Zhu
X.
Wang
Y.
Zhang
Y.
Kou
Z.
Wang
S.
Gao
S.
Novel importin-alpha family member Kpna7 is required for normal fertility and fecundity in the mouse
J. Biol. Chem.
2010
, vol. 
285
 (pg. 
33113
-
33122
)
[PubMed]
55
Yasuhara
N.
Shibazaki
N.
Tanaka
S.
Nagai
M.
Kamikawa
Y.
Oe
S.
Asally
M.
Kamachi
Y.
Kondoh
H.
Yoneda
Y.
Triggering neural differentiation of ES cells by subtype switching of importin-alpha
Nat. Cell Biol.
2007
, vol. 
9
 (pg. 
72
-
79
)
[PubMed]
56
Yasuhara
N.
Yamagishi
R.
Arai
Y.
Mehmood
R.
Kimoto
C.
Fujita
T.
Touma
K.
Kaneko
A.
Kamikawa
Y.
Moriyama
T.
, et al. 
Importin alpha subtypes determine differential transcription factor localization in embryonic stem cells maintenance
Dev. Cell
2013
, vol. 
26
 (pg. 
123
-
135
)
[PubMed]
57
Matsuura
Y.
Stewart
M.
Nup50/Npap60 function in nuclear protein import complex disassembly and importin recycling
EMBO J.
2005
, vol. 
24
 (pg. 
3681
-
3689
)
[PubMed]
58
Arjomand
A.
Baker
M.A.
Li
C.
Buckle
A.M.
Jans
D.A.
Loveland
K.L.
Miyamoto
Y.
The alpha-importome of mammalian germ cell maturation provides novel insights for importin biology
FASEB J.
2014
, vol. 
28
 (pg. 
3480
-
3493
)
[PubMed]
59
Hosokawa
K.
Nishi
M.
Sakamoto
H.
Tanaka
Y.
Kawata
M.
Regional distribution of importin subtype mRNA expression in the nervous system: study of early postnatal and adult mouse
Neuroscience
2008
, vol. 
157
 (pg. 
864
-
877
)
[PubMed]
60
Hogarth
C.A.
Calanni
S.
Jans
D.A.
Loveland
K.L.
Importin alpha mRNAs have distinct expression profiles during spermatogenesis
Dev. Dyn.
2006
, vol. 
235
 (pg. 
253
-
262
)
[PubMed]
61
Holt
J.E.
Ly-Huynh
J.D.
Efthymiadis
A.
Hime
G.R.
Loveland
K.L.
Jans
D.A.
Regulation of nuclear import during differentiation: the IMP alpha gene family and spermatogenesis
Curr. Genomics
2007
, vol. 
8
 (pg. 
323
-
334
)
[PubMed]
62
Shmidt
T.
Hampich
F.
Ridders
M.
Schultrich
S.
Hans
V.H.
Tenner
K.
Vilianovich
L.
Qadri
F.
Alenina
N.
Hartmann
E.
, et al. 
Normal brain development in importin-alpha5 deficient-mice
Nat. Cell Biol.
2007
, vol. 
9
 (pg. 
1337
-
1338; author reply 1339
)
[PubMed]
63
Gabriel
G.
Klingel
K.
Otte
A.
Thiele
S.
Hudjetz
B.
Arman-Kalcek
G.
Sauter
M.
Shmidt
T.
Rother
F.
Baumgarte
S.
, et al. 
Differential use of importin-alpha isoforms governs cell tropism and host adaptation of influenza virus
Nat. Commun.
2011
, vol. 
2
 pg. 
156
 
[PubMed]
64
Rother
F.
Shmidt
T.
Popova
E.
Krivokharchenko
A.
Hugel
S.
Vilianovich
L.
Ridders
M.
Tenner
K.
Alenina
N.
Kohler
M.
, et al. 
Importin alpha7 is essential for zygotic genome activation and early mouse development
PLoS ONE
2011
, vol. 
6
 pg. 
e18310
 
[PubMed]
65
Moriyama
T.
Nagai
M.
Oka
M.
Ikawa
M.
Okabe
M.
Yoneda
Y.
Targeted disruption of one of the importin alpha family members leads to female functional incompetence in delivery
FEBS J.
2011
, vol. 
278
 (pg. 
1561
-
1572
)
[PubMed]
66
Hugel
S.
Depping
R.
Dittmar
G.
Rother
F.
Cabot
R.
Sury
M.D.
Hartmann
E.
Bader
M.
Identification of importin alpha 7 specific transport cargoes using a proteomic screening approach
Mol. Cell. Proteomics
2014
, vol. 
13
 (pg. 
1286
-
1298
)
[PubMed]
67
Miyamoto
Y.
Baker
M.A.
Whiley
P.A.
Arjomand
A.
Ludeman
J.
Wong
C.
Jans
D.A.
Loveland
K.L.
Towards delineation of a developmental alpha-importome in the mammalian male germline
Biochim. Biophys. Acta
2013
, vol. 
1833
 (pg. 
731
-
742
)
[PubMed]
68
Conti
E.
Uy
M.
Leighton
L.
Blobel
G.
Kuriyan
J.
Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha
Cell
1998
, vol. 
94
 (pg. 
193
-
204
)
[PubMed]
69
Zachariae
U.
Grubmuller
H.
Importin-beta: structural and dynamic determinants of a molecular spring
Structure
2008
, vol. 
16
 (pg. 
906
-
915
)
[PubMed]
70
Andrade
M.A.
Petosa
C.
O'Donoghue
S.I.
Muller
C.W.
Bork
P.
Comparison of ARM and HEAT protein repeats
J. Mol. Biol.
2001
, vol. 
309
 (pg. 
1
-
18
)
[PubMed]
71
Conti
E.
Muller
C.W.
Stewart
M.
Karyopherin flexibility in nucleocytoplasmic transport
Curr. Opin. Struct. Biol.
2006
, vol. 
16
 (pg. 
237
-
244
)
[PubMed]
72
Forwood
J.K.
Lange
A.
Zachariae
U.
Marfori
M.
Preast
C.
Grubmuller
H.
Stewart
M.
Corbett
A.H.
Kobe
B.
Quantitative structural analysis of importin-beta flexibility: paradigm for solenoid protein structures
Structure
2010
, vol. 
18
 (pg. 
1171
-
1183
)
[PubMed]
73
Matsuura
Y.
Stewart
M.
Structural basis for the assembly of a nuclear export complex
Nature
2004
, vol. 
432
 (pg. 
872
-
877
)
[PubMed]
74
Fanara
P.
Hodel
M.R.
Corbett
A.H.
Hodel
A.E.
Quantitative analysis of nuclear localization signal (NLS)-importin alpha interaction through fluorescence depolarization. Evidence for auto-inhibitory regulation of NLS binding
J. Biol. Chem.
2000
, vol. 
275
 (pg. 
21218
-
21223
)
[PubMed]
75
Harreman
M.T.
Cohen
P.E.
Hodel
M.R.
Truscott
G.J.
Corbett
A.H.
Hodel
A.E.
Characterization of the auto-inhibitory sequence within the N-terminal domain of importin alpha
J. Biol. Chem.
2003
, vol. 
278
 (pg. 
21361
-
21369
)
[PubMed]
76
Harreman
M.T.
Hodel
M.R.
Fanara
P.
Hodel
A.E.
Corbett
A.H.
The auto-inhibitory function of importin alpha is essential in vivo
J. Biol. Chem.
2003
, vol. 
278
 (pg. 
5854
-
5863
)
[PubMed]
77
Friedrich
B.
Quensel
C.
Sommer
T.
Hartmann
E.
Kohler
M.
Nuclear localization signal and protein context both mediate importin alpha specificity of nuclear import substrates
Mol. Cell. Biol.
2006
, vol. 
26
 (pg. 
8697
-
8709
)
[PubMed]
78
Lange
A.
Mills
R.E.
Lange
C.J.
Stewart
M.
Devine
S.E.
Corbett
A.H.
Classical nuclear localization signals: definition, function, and interaction with importin alpha
J. Biol. Chem.
2007
, vol. 
282
 (pg. 
5101
-
5105
)
[PubMed]
79
Fischer
U.
Huber
J.
Boelens
W.C.
Mattaj
I.W.
Luhrmann
R.
The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs
Cell
1995
, vol. 
82
 (pg. 
475
-
483
)
[PubMed]
80
O'Neill
R.E.
Jaskunas
R.
Blobel
G.
Palese
P.
Moroianu
J.
Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import
J. Biol. Chem.
1995
, vol. 
270
 (pg. 
22701
-
22704
)
[PubMed]
81
Melen
K.
Fagerlund
R.
Franke
J.
Kohler
M.
Kinnunen
L.
Julkunen
I.
Importin alpha nuclear localization signal binding sites for STAT1, STAT2, and influenza A virus nucleoprotein
J. Biol. Chem.
2003
, vol. 
278
 (pg. 
28193
-
28200
)
[PubMed]
82
Ao
Z.
Danappa Jayappa
K.
Wang
B.
Zheng
Y.
Kung
S.
Rassart
E.
Depping
R.
Kohler
M.
Cohen
E.A.
Yao
X.
Importin alpha3 interacts with HIV-1 integrase and contributes to HIV-1 nuclear import and replication
J. Virol.
2010
, vol. 
84
 (pg. 
8650
-
8663
)
[PubMed]
83
Levin
A.
Hayouka
Z.
Friedler
A.
Loyter
A.
Transportin 3 and importin alpha are required for effective nuclear import of HIV-1 integrase in virus-infected cells
Nucleus
2010
, vol. 
1
 (pg. 
422
-
431
)
[PubMed]
84
Resa-Infante
P.
Gabriel
G.
The nuclear import machinery is a determinant of influenza virus host adaptation
Bioessays
2013
, vol. 
35
 (pg. 
23
-
27
)
[PubMed]
85
Hudjetz
B.
Gabriel
G.
Human-like PB2 627K influenza virus polymerase activity is regulated by importin-alpha1 and -alpha7
PLoS Pathog.
2012
, vol. 
8
 pg. 
e1002488
 
[PubMed]
86
Resa-Infante
P.
Thieme
R.
Ernst
T.
Arck
P.C.
Ittrich
H.
Reimer
R.
Gabriel
G.
Importin-alpha7 is required for enhanced influenza A virus replication in the alveolar epithelium and severe lung damage in mice
J. Virol.
2014
, vol. 
88
 (pg. 
8166
-
8179
)
87
Boivin
S.
Hart
D.J.
Interaction of the influenza A virus polymerase PB2 C-terminal region with importin alpha isoforms provides insights into host adaptation and polymerase assembly
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
10439
-
10448
)
[PubMed]
88
Kamata
M.
Nitahara-Kasahara
Y.
Miyamoto
Y.
Yoneda
Y.
Aida
Y.
Importin-alpha promotes passage through the nuclear pore complex of human immunodeficiency virus type 1 Vpr
J. Virol.
2005
, vol. 
79
 (pg. 
3557
-
3564
)
[PubMed]
89
Nitahara-Kasahara
Y.
Kamata
M.
Yamamoto
T.
Zhang
X.
Miyamoto
Y.
Muneta
K.
Iijima
S.
Yoneda
Y.
Tsunetsugu-Yokota
Y.
Aida
Y.
Novel nuclear import of Vpr promoted by importin alpha is crucial for human immunodeficiency virus type 1 replication in macrophages
J. Virol.
2007
, vol. 
81
 (pg. 
5284
-
5293
)
[PubMed]
90
Takeda
E.
Murakami
T.
Matsuda
G.
Murakami
H.
Zako
T.
Maeda
M.
Aida
Y.
Nuclear exportin receptor CAS regulates the NPI-1-mediated nuclear import of HIV-1 Vpr
PLoS ONE
2011
, vol. 
6
 pg. 
e27815
 
[PubMed]
91
Reid
S.P.
Leung
L.W.
Hartman
A.L.
Martinez
O.
Shaw
M.L.
Carbonnelle
C.
Volchkov
V.E.
Nichol
S.T.
Basler
C.F.
Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation
J. Virol.
2006
, vol. 
80
 (pg. 
5156
-
5167
)
[PubMed]
92
Chen
J.
Wu
M.
Zhang
X.
Zhang
W.
Zhang
Z.
Chen
L.
He
J.
Zheng
Y.
Chen
C.
Wang
F.
, et al. 
Hepatitis B virus polymerase impairs interferon-alpha-induced STA T activation through inhibition of importin-alpha5 and protein kinase C-delta
Hepatology
2013
, vol. 
57
 (pg. 
470
-
482
)
[PubMed]
93
Reid
S.P.
Valmas
C.
Martinez
O.
Sanchez
F.M.
Basler
C.F.
Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin alpha proteins with activated STAT1
J. Virol.
2007
, vol. 
81
 (pg. 
13469
-
13477
)
[PubMed]
94
Han
Z.
Boshra
H.
Sunyer
J.O.
Zwiers
S.H.
Paragas
J.
Harty
R.N.
Biochemical and functional characterization of the Ebola virus VP24 protein: implications for a role in virus assembly and budding
J. Virol.
2003
, vol. 
77
 (pg. 
1793
-
1800
)
[PubMed]
95
Frieman
M.
Yount
B.
Heise
M.
Kopecky-Bromberg
S.A.
Palese
P.
Baric
R.S.
Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane
J. Virol.
2007
, vol. 
81
 (pg. 
9812
-
9824
)
[PubMed]
96
Sims
A.C.
Tilton
S.C.
Menachery
V.D.
Gralinski
L.E.
Schafer
A.
Matzke
M.M.
Webb-Robertson
B.J.
Chang
J.
Luna
M.L.
Long
C.E.
, et al. 
Release of severe acute respiratory syndrome coronavirus nuclear import block enhances host transcription in human lung cells
J. Virol.
2013
, vol. 
87
 (pg. 
3885
-
3902
)
[PubMed]
97
Najarro
P.
Traktman
P.
Lewis
J.A.
Vaccinia virus blocks gamma interferon signal transduction: viral VH1 phosphatase reverses Stat1 activation
J. Virol.
2001
, vol. 
75
 (pg. 
3185
-
3196
)
[PubMed]
98
Koksal
A.C.
Cingolani
G.
Dimerization of Vaccinia virus VH1 is essential for dephosphorylation of STAT1 at tyrosine 701
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
14373
-
14382
)
[PubMed]
99
Koksal
A.C.
Nardozzi
J.D.
Cingolani
G.
Dimeric quaternary structure of the prototypical dual specificity phosphatase VH1
J. Biol. Chem.
2009
, vol. 
284
 (pg. 
10129
-
10137
)
[PubMed]
100
Dahl
E.
Kristiansen
G.
Gottlob
K.
Klaman
I.
Ebner
E.
Hinzmann
B.
Hermann
K.
Pilarsky
C.
Durst
M.
Klinkhammer-Schalke
M.
, et al. 
Molecular profiling of laser-microdissected matched tumor and normal breast tissue identifies karyopherin alpha2 as a potential novel prognostic marker in breast cancer
Clin. Cancer Res.
2006
, vol. 
12
 (pg. 
3950
-
3960
)
[PubMed]
101
Zheng
M.
Tang
L.
Huang
L.
Ding
H.
Liao
W.T.
Zeng
M.S.
Wang
H.Y.
Overexpression of karyopherin-2 in epithelial ovarian cancer and correlation with poor prognosis
Obstet. Gynecol.
2010
, vol. 
116
 (pg. 
884
-
891
)
[PubMed]
102
van der Watt
P.J.
Maske
C.P.
Hendricks
D.T.
Parker
M.I.
Denny
L.
Govender
D.
Birrer
M.J.
Leaner
V.D.
The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation
Int. J. Cancer
2009
, vol. 
124
 (pg. 
1829
-
1840
)
[PubMed]
103
Mortezavi
A.
Hermanns
T.
Seifert
H.H.
Baumgartner
M.K.
Provenzano
M.
Sulser
T.
Burger
M.
Montani
M.
Ikenberg
K.
Hofstadter
F.
, et al. 
KPNA2 expression is an independent adverse predictor of biochemical recurrence after radical prostatectomy
Clin. Cancer Res.
2011
, vol. 
17
 (pg. 
1111
-
1121
)
[PubMed]
104
Jensen
J.B.
Munksgaard
P.P.
Sorensen
C.M.
Fristrup
N.
Birkenkamp-Demtroder
K.
Ulhoi
B.P.
Jensen
K.M.
Orntoft
T.F.
Dyrskjot
L.
High expression of karyopherin-alpha2 defines poor prognosis in non-muscle-invasive bladder cancer and in patients with invasive bladder cancer undergoing radical cystectomy
Eur. Urol.
2011
, vol. 
59
 (pg. 
841
-
848
)
[PubMed]
105
Winnepenninckx
V.
Lazar
V.
Michiels
S.
Dessen
P.
Stas
M.
Alonso
S.R.
Avril
M.F.
Ortiz Romero
P.L.
Robert
T.
Balacescu
O.
, et al. 
Melanoma Group of the European Organization for Research and Treatment of Cancer Melanoma
Gene expression profiling of primary cutaneous melanoma and clinical outcome
J. Natl. Cancer Inst.
2006
, vol. 
98
 (pg. 
472
-
482
)
[PubMed]
106
Sakai
M.
Sohda
M.
Miyazaki
T.
Suzuki
S.
Sano
A.
Tanaka
N.
Inose
T.
Nakajima
M.
Kato
H.
Kuwano
H.
Significance of karyopherin-{alpha} 2 (KPNA2) expression in esophageal squamous cell carcinoma
Anticancer Res.
2010
, vol. 
30
 (pg. 
851
-
856
)
[PubMed]
107
Yoshitake
K.
Tanaka
S.
Mogushi
K.
Aihara
A.
Murakata
A.
Matsumura
S.
Mitsunori
Y.
Yasen
M.
Ban
D.
Noguchi
N.
, et al. 
Importin-alpha1 as a novel prognostic target for hepatocellular carcinoma
Ann. Surg. Oncol.
2011
, vol. 
18
 (pg. 
2093
-
2103
)
[PubMed]
108
Wang
C.I.
Wang
C.L.
Wang
C.W.
Chen
C.D.
Wu
C.C.
Liang
Y.
Tsai
Y.H.
Chang
Y.S.
Yu
J.S.
Yu
C.J.
Importin subunit alpha-2 is identified as a potential biomarker for non-small cell lung cancer by integration of the cancer cell secretome and tissue transcriptome
Int. J. Cancer
2011
, vol. 
128
 (pg. 
2364
-
2372
)
[PubMed]
109
Gousias
K.
Becker
A.J.
Simon
M.
Niehusmann
P.
Nuclear karyopherin a2: a novel biomarker for infiltrative astrocytomas
J. Neurooncol.
2012
, vol. 
109
 (pg. 
545
-
553
)
[PubMed]
110
Gousias
K.
Niehusmann
P.
Gielen
G.
Simon
M.
Bostrom
J.
KPNA2 predicts long term survival in patients with anaplastic oligoastrocytomas
J. Clin. Neurosci.
2014
, vol. 
21
 (pg. 
1719
-
1724
)
[PubMed]
111
Huang
L.
Wang
H.Y.
Li
J.D.
Wang
J.H.
Zhou
Y.
Luo
R.Z.
Yun
J.P.
Zhang
Y.
Jia
W.H.
Zheng
M.
KPNA2 promotes cell proliferation and tumorigenicity in epithelial ovarian carcinoma through upregulation of c-Myc and downregulation of FOXO3a
Cell Death Dis.
2013
, vol. 
4
 pg. 
e745
 
[PubMed]
112
van der Watt
P.J.
Ngarande
E.
Leaner
V.D.
Overexpression of Kpnbeta1 and Kpnalpha2 importin proteins in cancer derives from deregulated E2F activity
PLoS ONE
2011
, vol. 
6
 pg. 
e27723
 
[PubMed]
113
Perry
R.B.
Fainzilber
M.
Nuclear transport factors in neuronal function
Semin. Cell Dev. Biol.
2009
, vol. 
20
 (pg. 
600
-
606
)
[PubMed]
114
Hanz
S.
Perlson
E.
Willis
D.
Zheng
J.Q.
Massarwa
R.
Huerta
J.J.
Koltzenburg
M.
Kohler
M.
van-Minnen
J.
Twiss
J.L.
, et al. 
Axoplasmic importins enable retrograde injury signaling in lesioned nerve
Neuron
2003
, vol. 
40
 (pg. 
1095
-
1104
)
[PubMed]
115
Ben-Yaakov
K.
Dagan
S.Y.
Segal-Ruder
Y.
Shalem
O.
Vuppalanchi
D.
Willis
D.E.
Yudin
D.
Rishal
I.
Rother
F.
Bader
M.
, et al. 
Axonal transcription factors signal retrogradely in lesioned peripheral nerve
EMBO J.
2012
, vol. 
31
 (pg. 
1350
-
1363
)
[PubMed]
116
Paciorkowski
A.R.
Weisenberg
J.
Kelley
J.B.
Spencer
A.
Tuttle
E.
Ghoneim
D.
Thio
L.L.
Christian
S.L.
Dobyns
W.B.
Paschal
B.M.
Autosomal recessive mutations in nuclear transport factor KPNA7 are associated with infantile spasms and cerebellar malformation
Eur. J. Hum. Gen.
2014
, vol. 
22
 (pg. 
587
-
593
)
117
Roussos
P.
Katsel
P.
Davis
K.L.
Giakoumaki
S.G.
Lencz
T.
Malhotra
A.K.
Siever
L.J.
Bitsios
P.
Haroutunian
V.
Convergent findings for abnormalities of the NF-kappaB signaling pathway in schizophrenia
Neuropsychopharmacology
2013
, vol. 
38
 (pg. 
533
-
539
)
[PubMed]
118
Morris
C.P.
Baune
B.T.
Domschke
K.
Arolt
V.
Swagell
C.D.
Hughes
I.P.
Lawford
B.R.
McD Young
R.
Voisey
J.
KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence
Dis. Markers
2012
, vol. 
33
 (pg. 
163
-
170
)
[PubMed]
119
Zhang
H.
Ju
G.
Wei
J.
Hu
Y.
Liu
L.
Xu
Q.
Chen
Y.
Sun
Z.
Liu
S.
Yu
Y.
, et al. 
A combined effect of the KPNA3 and KPNB3 genes on susceptibility to schizophrenia
Neurosci. Lett.
2006
, vol. 
402
 (pg. 
173
-
175
)
[PubMed]
120
Lee
H.G.
Ueda
M.
Miyamoto
Y.
Yoneda
Y.
Perry
G.
Smith
M.A.
Zhu
X.
Aberrant localization of importin alpha1 in hippocampal neurons in Alzheimer disease
Brain Res.
2006
, vol. 
1124
 (pg. 
1
-
4
)
[PubMed]
121
Ahluwalia
A.
Narula
J.
Jones
M.K.
Deng
X.
Tarnawski
A.S.
Impaired angiogenesis in aging myocardial microvascular endothelial cells is associated with reduced importin alpha and decreased nuclear transport of HIF1 alpha: mechanistic implications
J. Physiol. Pharmacol.
2010
, vol. 
61
 (pg. 
133
-
139
)
[PubMed]
122
Pujol
G.
Soderqvist
H.
Radu
A.
Age-associated reduction of nuclear protein import in human fibroblasts
Biochem. Biophys. Res. Commun.
2002
, vol. 
294
 (pg. 
354
-
358
)
[PubMed]
123
Sun
X.
Icli
B.
Wara
A.K.
Belkin
N.
He
S.
Kobzik
L.
Hunninghake
G.M.
Vera
M.P.
Registry
M.
Blackwell
T.S.
, et al. 
MicroRNA-181b regulates NF-kappaB-mediated vascular inflammation
J. Clin. Invest.
2012
, vol. 
122
 (pg. 
1973
-
1990
)
[PubMed]
124
Fagerlund
R.
Melen
K.
Cao
X.
Julkunen
I.
NF-kappaB p52, RelB and c-Rel are transported into the nucleus via a subset of importin alpha molecules
Cell Signal.
2008
, vol. 
20
 (pg. 
1442
-
1451
)
[PubMed]
125
Sun
X.
He
S.
Wara
A.K.
Icli
B.
Shvartz
E.
Tesmenitsky
Y.
Belkin
N.
Li
D.
Blackwell
T.S.
Sukhova
G.K.
, et al. 
Systemic delivery of microRNA-181b inhibits nuclear factor-kappaB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice
Circ. Res.
2014
, vol. 
114
 (pg. 
32
-
40
)
[PubMed]
126
Theiss
A.L.
Jenkins
A.K.
Okoro
N.I.
Klapproth
J.M.
Merlin
D.
Sitaraman
S.V.
Prohibitin inhibits tumor necrosis factor alpha-induced nuclear factor-kappa B nuclear translocation via the novel mechanism of decreasing importin alpha3 expression
Mol. Biol. Cell
2009
, vol. 
20
 (pg. 
4412
-
4423
)
[PubMed]
127
Bao
H.
Chen
H.
Zhu
X.
Zhang
M.
Yao
G.
Yu
Y.
Qin
W.
Zeng
C.
Zen
K.
Liu
Z.
MiR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin alpha4 and alpha5 in IgA nephropathy
Kidney Int.
2014
, vol. 
85
 (pg. 
624
-
635
)
[PubMed]
128
Glinsky
G.V.
An SNP-guided microRNA map of fifteen common human disorders identifies a consensus disease phenocode aiming at principal components of the nuclear import pathway
Cell Cycle
2008
, vol. 
7
 (pg. 
2570
-
2583
)
[PubMed]
129
Huang
S.
Chang
I.S.
Lin
W.
Ye
W.
Luo
R.Z.
Lu
Z.
Lu
Y.
Zhang
K.
Liao
W.S.
Tao
T.
, et al. 
ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins
Biosci. Rep.
2010
, vol. 
30
 (pg. 
159
-
168
)
130
Wang
R.
Nan
Y.
Yu
Y.
Zhang
Y.J.
Porcine reproductive and respiratory syndrome virus Nsp1beta inhibits interferon-activated JAK/STAT signal transduction by inducing karyopherin-alpha1 degradation
J. Virol.
2013
, vol. 
87
 (pg. 
5219
-
5228
)
[PubMed]
131
Du
Y.
Bi
J.
Liu
J.
Liu
X.
Wu
X.
Jiang
P.
Yoo
D.
Zhang
Y.
Wu
J.
Wan
R.
, et al. 
3Cpro of foot-and-mouth disease virus antagonizes the interferon signaling pathway by blocking STAT1/STAT2 nuclear translocation
J. Virol.
2014
, vol. 
88
 (pg. 
4908
-
4920
)
[PubMed]
132
Jenkins
M.R.
Trapani
J.A.
Doherty
P.C.
Turner
S.J.
Granzyme K expressing cytotoxic T lymphocytes protects against influenza virus in granzyme AB−/− mice
Viral Immunol.
2008
, vol. 
21
 (pg. 
341
-
346
)
[PubMed]
133
Zhong
C.
Li
C.
Wang
X.
Toyoda
T.
Gao
G.
Fan
Z.
Granzyme K inhibits replication of influenza virus through cleaving the nuclear transport complex importin alpha1/beta dimer of infected host cells
Cell Death Differ.
2012
, vol. 
19
 (pg. 
882
-
890
)
[PubMed]
134
Miyamoto
Y.
Hieda
M.
Harreman
M.T.
Fukumoto
M.
Saiwaki
T.
Hodel
A.E.
Corbett
A.H.
Yoneda
Y.
Importin alpha can migrate into the nucleus in an importin beta- and Ran-independent manner
EMBO J.
2002
, vol. 
21
 (pg. 
5833
-
5842
)
[PubMed]
135
Kim
B.J.
Lee
H.
Caspase-mediated cleavage of importin-alpha increases its affinity for MCM and downregulates DNA synthesis by interrupting the binding of MCM to chromatin
Biochim. Biophys. Acta
2008
, vol. 
1783
 (pg. 
2287
-
2293
)
[PubMed]
136
Simkus
C.
Makiya
M.
Jones
J.M.
Karyopherin alpha 1 is a putative substrate of the RAG1 ubiquitin ligase
Mol. Immunol.
2009
, vol. 
46
 (pg. 
1319
-
1325
)
[PubMed]
137
Spanopoulou
E.
Cortes
P.
Shih
C.
Huang
C.M.
Silver
D.P.
Svec
P.
Baltimore
D.
Localization, interaction, and RNA binding properties of the V(D)J recombination-activating proteins RAG1 and RAG2
Immunity
1995
, vol. 
3
 (pg. 
715
-
726
)
[PubMed]
138
Nardozzi
J.D.
Lott
K.
Cingolani
G.
Phosphorylation meets nuclear import: a review
Cell Commun. Signal.
2010
, vol. 
8
 pg. 
32
 
[PubMed]
139
Kitamura
R.
Sekimoto
T.
Ito
S.
Harada
S.
Yamagata
H.
Masai
H.
Yoneda
Y.
Yanagi
K.
Nuclear import of Epstein–Barr virus nuclear antigen 1 mediated by NPI-1 (Importin alpha5) is up- and down-regulated by phosphorylation of the nuclear localization signal for which Lys379 and Arg380 are essential
J. Virol.
2006
, vol. 
80
 (pg. 
1979
-
1991
)
[PubMed]
140
Bannister
A.J.
Miska
E.A.
Gorlich
D.
Kouzarides
T.
Acetylation of importin-alpha nuclear import factors by CBP/p300
Curr. Biol.
2000
, vol. 
10
 (pg. 
467
-
470
)
[PubMed]
141
Wang
W.
Yang
X.
Kawai
T.
Lopez de Silanes
I.
Mazan-Mamczarz
K.
Chen
P.
Chook
Y.M.
Quensel
C.
Kohler
M.
Gorospe
M.
AMP-activated protein kinase-regulated phosphorylation and acetylation of importin alpha1: involvement in the nuclear import of RNA-binding protein HuR
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
48376
-
48388
)
[PubMed]
142
Nadler
S.G.
Tritschler
D.
Haffar
O.K.
Blake
J.
Bruce
A.G.
Cleaveland
J.S.
Differential expression and sequence-specific interaction of karyopherin alpha with nuclear localization sequences
J. Biol. Chem.
1997
, vol. 
272
 (pg. 
4310
-
4315
)
[PubMed]
143
Lin
Y.Z.
Yao
S.Y.
Veach
R.A.
Torgerson
T.R.
Hawiger
J.
Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence
J. Biol. Chem.
1995
, vol. 
270
 (pg. 
14255
-
14258
)
[PubMed]
144
Zienkiewicz
J.
Armitage
A.
Hawiger
J.
Targeting nuclear import shuttles, importins/karyopherins alpha by a peptide mimicking the NFkappaB1/p50 nuclear localization sequence
J. Am. Heart Assoc.
2013
, vol. 
2
 pg. 
e000386
 
[PubMed]
145
Liu
D.
Zienkiewicz
J.
DiGiandomenico
A.
Hawiger
J.
Suppression of acute lung inflammation by intracellular peptide delivery of a nuclear import inhibitor
Mol. Ther.
2009
, vol. 
17
 (pg. 
796
-
802
)
[PubMed]
146
Torgerson
T.R.
Colosia
A.D.
Donahue
J.P.
Lin
Y.Z.
Hawiger
J.
Regulation of NF-kappa B, AP-1, NFAT, and STAT1 nuclear import in T lymphocytes by noninvasive delivery of peptide carrying the nuclear localization sequence of NF-kappa B p50
J. Immunol.
1998
, vol. 
161
 (pg. 
6084
-
6092
)
[PubMed]
147
Kosugi
S.
Hasebe
M.
Entani
T.
Takayama
S.
Tomita
M.
Yanagawa
H.
Design of peptide inhibitors for the importin alpha/beta nuclear import pathway by activity-based profiling
Chem. Biol.
2008
, vol. 
15
 (pg. 
940
-
949
)
[PubMed]
148
Tay
M.Y.
Fraser
J.E.
Chan
W.K.
Moreland
N.J.
Rathore
A.P.
Wang
C.
Vasudevan
S.G.
Jans
D.A.
Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin
Antiviral Res.
2013
, vol. 
99
 (pg. 
301
-
306
)
[PubMed]
149
Wagstaff
K.M.
Sivakumaran
H.
Heaton
S.M.
Harrich
D.
Jans
D.A.
Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus
Biochem. J.
2012
, vol. 
443
 (pg. 
851
-
856
)
[PubMed]
150
Pettersen
E.F.
Goddard
T.D.
Huang
C.C.
Couch
G.S.
Greenblatt
D.M.
Meng
E.C.
Ferrin
T.E.
UCSF Chimera–a visualization system for exploratory research and analysis
J. Comput. Chem.
2004
, vol. 
25
 (pg. 
1605
-
1612
)
[PubMed]
151
Page
R.D.
TreeView: an application to display phylogenetic trees on personal computers
Comput. Appl. Biosci.
1996
, vol. 
12
 (pg. 
357
-
358
)
[PubMed]
152
Dolinsky
T.J.
Nielsen
J.E.
McCammon
J.A.
Baker
N.A.
PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations
Nucleic Acids Res.
2004
, vol. 
32
 (pg. 
W665
-
W667
)
[PubMed]
153
Reference deleted
[PubMed]
154
Wang
P.
Palese
P.
O'Neill
R.E.
The NPI-1/NPI-3 (karyopherin alpha) binding site on the influenza a virus nucleoprotein NP is a nonconventional nuclear localization signal
J. Virol.
1997
, vol. 
71
 (pg. 
1850
-
1856
)
[PubMed]
155
Nachury
M.V.
Ryder
U.W.
Lamond
A.I.
Weis
K.
Cloning and characterization of hSRP1 gamma, a tissue-specific nuclear transport factor
Proc. Natl. Acad. Sci. U. S. A.
1998
, vol. 
95
 (pg. 
582
-
587
)
[PubMed]
156
Ushijima
R.
Sakaguchi
N.
Kano
A.
Maruyama
A.
Miyamoto
Y.
Sekimoto
T.
Yoneda
Y.
Ogino
K.
Tachibana
T.
Extracellular signal-dependent nuclear import of STAT3 is mediated by various importin alphas
Biochem. Biophys. Res. Commun.
2005
, vol. 
330
 (pg. 
880
-
886
)
[PubMed]
157
Tachibana
T.
Hieda
M.
Miyamoto
Y.
Kose
S.
Imamoto
N.
Yoneda
Y.
Recycling of importin alpha from the nucleus is suppressed by loss of RCC1 function in living mammalian cells
Cell Struct. Funct.
2000
, vol. 
25
 (pg. 
115
-
123
)
[PubMed]
158
Maas
S.
Gommans
W.M.
Identification of a selective nuclear import signal in adenosine deaminases acting on RNA
Nucleic Acids Res.
2009
, vol. 
37
 (pg. 
5822
-
5829
)
[PubMed]
159
Ilmarinen
T.
Melen
K.
Kangas
H.
Julkunen
I.
Ulmanen
I.
Eskelin
P.
The monopartite nuclear localization signal of autoimmune regulator mediates its nuclear import and interaction with multiple importin alpha molecules
FEBS J.
2006
, vol. 
273
 (pg. 
315
-
324
)
[PubMed]
160
Ye
W.
Lin
W.
Tartakoff
A.M.
Ma
Q.
Tao
T.
Nuclear import of aristaless-related homeobox protein via its NLS1 regulates its transcriptional function
Mol. Cell. Biochem.
2013
, vol. 
381
 (pg. 
221
-
231
)
[PubMed]
161
Li
S.
Ku
C.Y.
Farmer
A.A.
Cong
Y.S.
Chen
C.F.
Lee
W.H.
Identification of a novel cytoplasmic protein that specifically binds to nuclear localization signal motifs
J. Biol. Chem.
1998
, vol. 
273
 (pg. 
6183
-
6189
)
[PubMed]
162
Rivera
J.
Megias
D.
Navas
C.
Bravo
J.
Identification of essential sequences for cellular localization in BRMS1 metastasis suppressor
PLoS ONE
2009
, vol. 
4
 pg. 
e6433
 
[PubMed]
163
Li
F.Q.
Mofunanya
A.
Fischer
V.
Hall
J.
Takemaru
K.
Nuclear-cytoplasmic shuttling of Chibby controls beta-catenin signaling
Mol. Biol. Cell
2010
, vol. 
21
 (pg. 
311
-
322
)
[PubMed]
164
Dissanayake
K.
Toth
R.
Blakey
J.
Olsson
O.
Campbell
D.G.
Prescott
A.R.
MacKintosh
C.
ERK/p90(RSK)/14-3-3 signalling has an impact on expression of PEA3 Ets transcription factors via the transcriptional repressor capicua
Biochem. J.
2011
, vol. 
433
 (pg. 
515
-
525
)
[PubMed]
165
Lai
K.O.
Zhao
Y.
Ch'ng
T.H.
Martin
K.C.
Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons
Proc. Natl. Acad. Sci. U. S. A.
2008
, vol. 
105
 (pg. 
17175
-
17180
)
[PubMed]
166
Yeung
P.L.
Chen
L.Y.
Tsai
S.C.
Zhang
A.
Chen
J.D.
Daxx contains two nuclear localization signals and interacts with importin alpha3
J. Cell. Biochem.
2008
, vol. 
103
 (pg. 
456
-
470
)
[PubMed]
167
Okada
M.
Hozumi
Y.
Ichimura
T.
Tanaka
T.
Hasegawa
H.
Yamamoto
M.
Takahashi
N.
Iseki
K.
Yagisawa
H.
Shinkawa
T.
, et al. 
Interaction of nucleosome assembly proteins abolishes nuclear localization of DGKzeta by attenuating its association with importins
Exp. Cell Res.
2011
, vol. 
317
 (pg. 
2853
-
2863
)
[PubMed]
168
Papadopoulos
C.
Arato
K.
Lilienthal
E.
Zerweck
J.
Schutkowski
M.
Chatain
N.
Muller-Newen
G.
Becker
W.
de la Luna
S.
Splice variants of the dual specificity tyrosine phosphorylation-regulated kinase 4 (DYRK4) differ in their subcellular localization and catalytic activity
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
5494
-
5505
)
[PubMed]
169
Mehmood
R.
Yasuhara
N.
Fukumoto
M.
Oe
S.
Tachibana
T.
Yoneda
Y.
Cross-talk between distinct nuclear import pathways enables efficient nuclear import of E47 in conjunction with its partner transcription factors
Mol. Biol. Cell
2011
, vol. 
22
 (pg. 
3715
-
3724
)
[PubMed]
170
Song
N.
Ding
Y.
Zhuo
W.
He
T.
Fu
Z.
Chen
Y.
Song
X.
Fu
Y.
Luo
Y.
The nuclear translocation of endostatin is mediated by its receptor nucleolin in endothelial cells
Angiogenesis
2012
, vol. 
15
 (pg. 
697
-
711
)
[PubMed]
171
Zhen
Y.
Sorensen
V.
Skjerpen
C.S.
Haugsten
E.M.
Jin
Y.
Walchli
S.
Olsnes
S.
Wiedlocha
A.
Nuclear import of exogenous FGF1 requires the ER-protein LRRC59 and the importins Kpnalpha1 and Kpnbeta1
Traffic
2012
, vol. 
13
 (pg. 
650
-
664
)
[PubMed]
172
Guillemain
G.
Munoz-Alonso
M.J.
Cassany
A.
Loizeau
M.
Faussat
A.M.
Burnol
A.F.
Leturque
A.
Karyopherin alpha2: a control step of glucose-sensitive gene expression in hepatic cells
Biochem. J.
2002
, vol. 
364
 (pg. 
201
-
209
)
[PubMed]
173
Melzer
N.
Villmann
C.
Becker
K.
Harvey
K.
Harvey
R.J.
Vogel
N.
Kluck
C.J.
Kneussel
M.
Becker
C.M.
Multifunctional basic motif in the glycine receptor intracellular domain induces subunit-specific sorting
J. Biol. Chem.
2010
, vol. 
285
 (pg. 
3730
-
3739
)
[PubMed]
174
Shabman
R.S.
Gulcicek
E.E.
Stone
K.L.
Basler
C.F.
The Ebola virus VP24 protein prevents hnRNP C1/C2 binding to karyopherin alpha1 and partially alters its nuclear import
J. Infect. Dis.
2011
, vol. 
204
 
suppl 3
(pg. 
S904
-
S910
)
[PubMed]
175
Umegaki
N.
Tamai
K.
Nakano
H.
Moritsugu
R.
Yamazaki
T.
Hanada
K.
Katayama
I.
Kaneda
Y.
Differential regulation of karyopherin alpha 2 expression by TGF-beta1 and IFN-gamma in normal human epidermal keratinocytes: evident contribution of KPNA2 for nuclear translocation of IRF-1
J. Invest. Dermatol.
2007
, vol. 
127
 (pg. 
1456
-
1464
)
[PubMed]
176
Banninger
G.
Reich
N.C.
STAT2 nuclear trafficking
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
39199
-
39206
)
[PubMed]
177
Perez-Villar
J.J.
O'Day
K.
Hewgill
D.H.
Nadler
S.G.
Kanner
S.B.
Nuclear localization of the tyrosine kinase Itk and interaction of its SH3 domain with karyopherin alpha (Rch1alpha)
Int. Immunol.
2001
, vol. 
13
 (pg. 
1265
-
1274
)
[PubMed]
178
Misheva
M.
Kaur
G.
Ngoei
K.R.
Yeap
Y.Y.
Ng
I.H.
Wagstaff
K.M.
Ng
D.C.
Jans
D.A.
Bogoyevitch
M.A.
Intracellular mobility and nuclear trafficking of the stress-activated kinase JNK1 are impeded by hyperosmotic stress
Biochim. Biophys. Acta
2014
, vol. 
1843
 (pg. 
253
-
264
)
[PubMed]
179
Sun
Z.
Wu
T.
Zhao
F.
Lau
A.
Birch
C.M.
Zhang
D.D.
KPNA6 (Importin {alpha}7)-mediated nuclear import of Keap1 represses the Nrf2-dependent antioxidant response
Mol. Cell. Biol.
2011
, vol. 
31
 (pg. 
1800
-
1811
)
[PubMed]
180
Mahalakshmi
R.N.
Nagashima
K.
Ng
M.Y.
Inagaki
N.
Hunziker
W.
Beguin
P.
Nuclear transport of Kir/Gem requires specific signals and importin alpha5 and is regulated by calmodulin and predicted serine phosphorylations
Traffic
2007
, vol. 
8
 (pg. 
1150
-
1163
)
[PubMed]
181
Jin
Y.
Kim
T.Y.
Kim
M.S.
Kim
M.A.
Park
S.H.
Jang
Y.K.
Nuclear import of human histone lysine-specific demethylase LSD1
J. Biochem.
2014
, vol. 
156
 (pg. 
305
-
313
)
182
Nakamura
S.
Hayashi
K.
Iwasaki
K.
Fujioka
T.
Egusa
H.
Yatani
H.
Sobue
K.
Nuclear import mechanism for myocardin family members and their correlation with vascular smooth muscle cell phenotype
J. Biol. Chem.
2010
, vol. 
285
 (pg. 
37314
-
37323
)
[PubMed]
183
Tseng
S.F.
Chang
C.Y.
Wu
K.J.
Teng
S.C.
Importin KPNA2 is required for proper nuclear localization and multiple functions of NBS1
J. Biol. Chem.
2005
, vol. 
280
 (pg. 
39594
-
39600
)
[PubMed]
184
Liang
P.
Zhang
H.
Wang
G.
Li
S.
Cong
S.
Luo
Y.
Zhang
B.
KPNB1, XPO7 and IPO8 mediate the translocation of NF-kappaB/p65 into the nucleus
Traffic
2013
, vol. 
14
 (pg. 
1132
-
1143
)
[PubMed]
185
Huenniger
K.
Kramer
A.
Soom
M.
Chang
I.
Kohler
M.
Depping
R.
Kehlenbach
R.H.
Kaether
C.
Notch1 signaling is mediated by importins alpha 3, 4, and 7
Cell. Mol. Life Sci.
2010
, vol. 
67
 (pg. 
3187
-
3196
)
[PubMed]
186
Grundt
K.
Haga
I.V.
Huitfeldt
H.S.
Ostvold
A.C.
Identification and characterization of two putative nuclear localization signals (NLS) in the DNA-binding protein NUCKS
Biochim. Biophys. Acta
2007
, vol. 
1773
 (pg. 
1398
-
1406
)
[PubMed]
187
Ghosh
S.
Vassilev
A.P.
Zhang
J.
Zhao
Y.
DePamphilis
M.L.
Assembly of the human origin recognition complex occurs through independent nuclear localization of its components
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
23831
-
23841
)
[PubMed]
188
Sekimoto
T.
Fukumoto
M.
Yoneda
Y.
14-3-3 suppresses the nuclear localization of threonine 157-phosphorylated p27(Kip1)
EMBO J.
2004
, vol. 
23
 (pg. 
1934
-
1942
)
[PubMed]
189
Marchenko
N.D.
Hanel
W.
Li
D.
Becker
K.
Reich
N.
Moll
U.M.
Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-alpha3 binding
Cell Death Differ.
2010
, vol. 
17
 (pg. 
255
-
267
)
[PubMed]
190
Kumar
G.R.
Shum
L.
Glaunsinger
B.A.
Importin alpha-mediated nuclear import of cytoplasmic poly(A) binding protein occurs as a direct consequence of cytoplasmic mRNA depletion
Mol. Cell. Biol.
2011
, vol. 
31
 (pg. 
3113
-
3125
)
[PubMed]
191
Zhou
Y.
Fang
L.
Du
D.
Zhou
W.
Feng
X.
Chen
J.
Zhang
Z.
Chen
Z.
Proteome identification of binding-partners interacting with cell polarity protein Par3 in Jurkat cells
Acta Biochim. Biophys. Sin.
2008
, vol. 
40
 (pg. 
729
-
739
)
192
Haenni
S.S.
Altmeyer
M.
Hassa
P.O.
Valovka
T.
Fey
M.
Hottiger
M.O.
Importin alpha binding and nuclear localization of PARP-2 is dependent on lysine 36, which is located within a predicted classical NLS
BMC Cell Biol.
2008
, vol. 
9
 pg. 
39
 
[PubMed]
193
Lufei
C.
Cao
X.
Nuclear import of Pin1 is mediated by a novel sequence in the PPIase domain
FEBS Lett.
2009
, vol. 
583
 (pg. 
271
-
276
)
[PubMed]
194
Yang
W.
Zheng
Y.
Xia
Y.
Ji
H.
Chen
X.
Guo
F.
Lyssiotis
C.A.
Aldape
K.
Cantley
L.C.
Lu
Z.
ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect
Nat. Cell Biol.
2012
, vol. 
14
 (pg. 
1295
-
1304
)
[PubMed]
195
Yeung
P.L.
Zhang
A.
Chen
J.D.
Nuclear localization of coactivator RAC3 is mediated by a bipartite NLS and importin alpha3
Biochem. Biophys. Res. Commun.
2006
, vol. 
348
 (pg. 
13
-
24
)
[PubMed]
196
Welch
K.
Franke
J.
Kohler
M.
Macara
I.G.
RanBP3 contains an unusual nuclear localization signal that is imported preferentially by importin-alpha3
Mol. Cell. Biol.
1999
, vol. 
19
 (pg. 
8400
-
8411
)
[PubMed]
197
Talcott
B.
Moore
M.S.
The nuclear import of RCC1 requires a specific nuclear localization sequence receptor, karyopherin alpha3/Qip
J. Biol. Chem.
2000
, vol. 
275
 (pg. 
10099
-
10104
)
[PubMed]
198
Aratani
S.
Oishi
T.
Fujita
H.
Nakazawa
M.
Fujii
R.
Imamoto
N.
Yoneda
Y.
Fukamizu
A.
Nakajima
T.
The nuclear import of RNA helicase A is mediated by importin-alpha3
Biochem. Biophys. Res. Commun.
2006
, vol. 
340
 (pg. 
125
-
133
)
[PubMed]
199
McConville
J.F.
Fernandes
D.J.
Churchill
J.
Dewundara
S.
Kogut
P.
Shah
S.
Fuchs
G.
Kedainis
D.
Bellam
S.K.
Patel
N.M.
, et al. 
Nuclear import of serum response factor in airway smooth muscle
Am. J. Respir. Cell Mol. Biol.
2011
, vol. 
45
 (pg. 
453
-
458
)
[PubMed]
200
Qu
D.
Zhang
Y.
Ma
J.
Guo
K.
Li
R.
Yin
Y.
Cao
X.
Park
D.S.
The nuclear localization of SET mediated by impalpha3/impbeta attenuates its cytosolic toxicity in neurons
J. Neurochem.
2007
, vol. 
103
 (pg. 
408
-
422
)
[PubMed]
201
Ma
J.
Cao
X.
Regulation of Stat3 nuclear import by importin alpha5 and importin alpha7 via two different functional sequence elements
Cell Signal.
2006
, vol. 
18
 (pg. 
1117
-
1126
)
[PubMed]
202
Liu
L.
McBride
K.M.
Reich
N.C.
STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3
Proc. Natl. Acad. Sci. U. S. A.
2005
, vol. 
102
 (pg. 
8150
-
8155
)
[PubMed]
203
Shin
H.Y.
Reich
N.C.
Dynamic trafficking of STAT5 depends on an unconventional nuclear localization signal
J. Cell Sci.
2013
, vol. 
126
 (pg. 
3333
-
3343
)
[PubMed]
204
Chen
H.C.
Reich
N.C.
Live cell imaging reveals continuous STAT6 nuclear trafficking
J. Immunol.
2010
, vol. 
185
 (pg. 
64
-
70
)
[PubMed]
205
Nishinaka
Y.
Masutani
H.
Oka
S.
Matsuo
Y.
Yamaguchi
Y.
Nishio
K.
Ishii
Y.
Yodoi
J.
Importin alpha1 (Rch1) mediates nuclear translocation of thioredoxin-binding protein-2/vitamin D(3)-up-regulated protein 1
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
37559
-
37565
)
[PubMed]
206
Snow
C.J.
Dar
A.
Dutta
A.
Kehlenbach
R.H.
Paschal
B.M.
Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport
J. Cell Biol.
2013
, vol. 
201
 (pg. 
541
-
557
)
[PubMed]
207
Depping
R.
Schindler
S.G.
Jacobi
C.
Kirschner
K.M.
Scholz
H.
Nuclear transport of Wilms' tumour protein Wt1 involves importins alpha and beta
Cell Physiol. Biochem.
2012
, vol. 
29
 (pg. 
223
-
232
)
[PubMed]
208
Li
Z.
Musich
P.R.
Cartwright
B.M.
Wang
H.
Zou
Y.
UV-induced nuclear import of XPA is mediated by importin-alpha4 in an ATR-dependent manner
PLoS ONE
2013
, vol. 
8
 pg. 
e68297
 
[PubMed]
209
Hatayama
M.
Tomizawa
T.
Sakai-Kato
K.
Bouvagnet
P.
Kose
S.
Imamoto
N.
Yokoyama
S.
Utsunomiya-Tate
N.
Mikoshiba
K.
Kigawa
T.
, et al. 
Functional and structural basis of the nuclear localization signal in the ZIC3 zinc finger domain
Hum. Mol. Genet.
2008
, vol. 
17
 (pg. 
3459
-
3473
)
[PubMed]
210
Donaldson
N.S.
Daniel
Y.
Kelly
K.F.
Graham
M.
Daniel
J.M.
Nuclear trafficking of the POZ-ZF protein Znf131
Biochim. Biophys. Acta
2007
, vol. 
1773
 (pg. 
546
-
555
)
[PubMed]
211
Kohler
M.
Gorlich
D.
Hartmann
E.
Franke
J.
Adenoviral E1A protein nuclear import is preferentially mediated by importin alpha3 in vitro
Virology
2001
, vol. 
289
 (pg. 
186
-
191
)
[PubMed]
212
Marshall
K.S.
Cohen
M.J.
Fonseca
G.J.
Todorovic
B.
King
C.R.
Yousef
A.F.
Zhang
Z.
Mymryk
J.S.
Identification and characterization of multiple conserved nuclear localization signals within adenovirus E1A
Virology
2014
, vol. 
454–455
 (pg. 
206
-
214
)
213
Paterson
C.P.
Ayalew
L.E.
Tikoo
S.K.
Mapping of nuclear import signal and importin alpha3 binding regions of 52K protein of bovine adenovirus-3
Virology
2012
, vol. 
432
 (pg. 
63
-
72
)
[PubMed]
214
Thomas
S.
Rai
J.
John
L.
Schaefer
S.
Pützer
B.M.
Herchenröder
O.
Chikungunya virus capsid protein contains nuclear import and export signals
Virol. J.
2013
, vol. 
10
 (pg. 
210
-
269
)
[PubMed]
215
Taylor
S.L.
Frias-Staheli
N.
Garcia-Sastre
A.
Schmaljohn
C.S.
Hantaan virus nucleocapsid protein binds to importin alpha proteins and inhibits tumor necrosis factor alpha-induced activation of nuclear factor kappa B
J. Virol.
2009
, vol. 
83
 (pg. 
1271
-
1279
)
[PubMed]
216
Hearps
A.C.
Jans
D.A.
HIV-1 integrase is capable of targeting DNA to the nucleus via an importin alpha/beta-dependent mechanism
Biochem. J.
2006
, vol. 
398
 (pg. 
475
-
484
)
[PubMed]
217
Isegawa
Y.
Miyamoto
Y.
Yasuda
Y.
Semi
K.
Tsujimura
K.
Fukunaga
R.
Ohshima
A.
Horiguchi
Y.
Yoneda
Y.
Sugimoto
N.
Characterization of the human herpesvirus 6 U69 gene product and identification of its nuclear localization signal
J. Virol.
2008
, vol. 
82
 (pg. 
710
-
718
)
[PubMed]
218
Bian
X.L.
Rosas-Acosta
G.
Wu
Y.C.
Wilson
V.G.
Nuclear import of bovine papillomavirus type 1 E1 protein is mediated by multiple alpha importins and is negatively regulated by phosphorylation near a nuclear localization signal
J. Virol.
2007
, vol. 
81
 (pg. 
2899
-
2908
)
[PubMed]
219
Bian
X.L.
Wilson
V.G.
Common importin alpha specificity for papillomavirus E2 proteins
Virus Res.
2010
, vol. 
150
 (pg. 
135
-
137
)
[PubMed]
220
Shaw
M.L.
Cardenas
W.B.
Zamarin
D.
Palese
P.
Basler
C.F.
Nuclear localization of the Nipah virus W protein allows for inhibition of both virus- and toll-like receptor 3-triggered signaling pathways
J. Virol.
2005
, vol. 
79
 (pg. 
6078
-
6088
)
[PubMed]
221
Montgomery
S.A.
Johnston
R.E.
Nuclear import and export of Venezuelan equine encephalitis virus nonstructural protein 2
J. Virol.
2007
, vol. 
81
 (pg. 
10268
-
10279
)
[PubMed]