SUMOylation, a reversible process used as a ‘fine-tuning’ mechanism to regulate the role of multiple proteins, is conserved throughout evolution. This post-translational modification affects several cellular processes by the modulation of subcellular localization, activity or stability of a variety of substrates. A growing number of proteins have been identified as targets for SUMOylation, although, for many of them, the role of SUMO conjugation on their function is unknown. The use of model systems might facilitate the study of SUMOylation implications in vivo. In the present paper, we have compiled what is known about SUMOylation in Drosophila melanogaster, where the use of genetics provides new insights on SUMOylation's biological roles.

Introduction

SUMOylation is an essential cellular process conserved in all eukaryotic organisms analysed to date. In Drosophila, all of the components of the SUMOylation pathway have been identified, and their function has been studied (Table 1). The in vivo analysis of SUMOylation in the fruitfly presents a number of advantages. On one hand, gene redundancy is lower in Drosophila when compared with vertebrate models, which simplifies functional analysis. On the other hand, and related to the genetic accessibility of this organism, the various components of the pathway have been implicated in multiple cellular and physiological processes by means of genome-wide genetic screens performed in vivo. The information derived from these screenings will be, in many instances, translatable to vertebrate models. In the present review, we will show the components of the SUMOylation pathway identified in Drosophila and summarize the cellular and developmental roles in which these components have been involved.

Table 1
SUMOylation pathway components in Drosophila

EGFR, epidermal growth factor receptor.

Gene CG accession number Homologues Function Biological processes Reference(s) 
smt3 CG4494 SUMO-3 SUMO moiety Cell proliferation or survival; chromatin modification; embryogenesis; EGFR signalling; immune response; lysosomal transport; oogenesis; wing morphogenesis [1,2,6,31,33,35,53,54,56,57
Ulp1 CG12359 Sentrin/SUMO-specific protease 1 Isopeptidase Smt3-conjugates nucleocytoplasmic shuttling [15,33
Aos1 CG12276 Activating enzyme subunit 1 E1A-activating − [2,7,52
Uba2 CG7528 Activating enzyme subunit 2 E1B-activating − [2,7,52
lesswright CG3018 UBC9; ubiquitin-conjugating enzyme E2 E2-conjugating Cell proliferation; chromatin modification; embryogenesis; immune response; wing morphogenesis [6,11,3034,36,37,52,55
tonalli CG7958 Zimp7 and Zimp10; retinoic acid-induced 17 E3 ligase Chromatin modification [16,21
Suppressor of variegation 210 CG8068 PIAS3 E3 ligase Chromatin modification and chromosomal inheritance; negative regulation of JAK/STAT signalling; wing morphogenesis [2225,2729,31,58
Gene CG accession number Homologues Function Biological processes Reference(s) 
smt3 CG4494 SUMO-3 SUMO moiety Cell proliferation or survival; chromatin modification; embryogenesis; EGFR signalling; immune response; lysosomal transport; oogenesis; wing morphogenesis [1,2,6,31,33,35,53,54,56,57
Ulp1 CG12359 Sentrin/SUMO-specific protease 1 Isopeptidase Smt3-conjugates nucleocytoplasmic shuttling [15,33
Aos1 CG12276 Activating enzyme subunit 1 E1A-activating − [2,7,52
Uba2 CG7528 Activating enzyme subunit 2 E1B-activating − [2,7,52
lesswright CG3018 UBC9; ubiquitin-conjugating enzyme E2 E2-conjugating Cell proliferation; chromatin modification; embryogenesis; immune response; wing morphogenesis [6,11,3034,36,37,52,55
tonalli CG7958 Zimp7 and Zimp10; retinoic acid-induced 17 E3 ligase Chromatin modification [16,21
Suppressor of variegation 210 CG8068 PIAS3 E3 ligase Chromatin modification and chromosomal inheritance; negative regulation of JAK/STAT signalling; wing morphogenesis [2225,2729,31,58

The SUMOylation machinery in Drosophila

Unique orthologues for SUMO (small ubiquitin-related modifier) and for the isopeptidase, activating and conjugating enzymes have been identified in the fruitfly (Table 1). Drosophila Smt3 is closely related to the vertebrate homologue SUMO-3 and is expressed throughout development, being more prominent during embryogenesis and in adult females [14]. High levels of smt3 transcript and protein are maternally inherited and accumulate in the preblastoderm embryos, appearing uniformly distributed throughout the embryo at cellular blastoderm and gastrulation stages. The protein accumulates in the cytoplasm initially and rapidly goes to the nuclei where it localizes to dots. Later, the transcript accumulates preferentially in the CNS (central nervous system) and in the gonads [3,5]. In interphase nuclei, Smt3 can accumulate on the chromosomes [6] and, during mitosis, it is redistributed in the cytoplasm and localizes to the midbody during cytokinesis [3,7].

Other orthologous of the vertebrate SUMOylation machinery, such as Ulp1, Aos1, Uba2 and Lesswright (Lwr), are also enriched during embryogenesis, preferentially in the CNS and gonads [3,5,712]. They are also preferentially expressed in females [13] and in undifferentiated tissues [14]. Ulp1 localizes to the nucleoplasmic face of the nuclear pore complex in S2 cells, which is related to its role in nuclear transport [15].

The identification of E3 ligases is based on sequence homology with their vertebrate homologues. Tonalli (Tna) is the orthologue of Zimp7 and Zimp10, two novel human PIAS [protein inhibitor of activated STAT (signal transducer and activator of transcription)]-like proteins that contain a SP-RING (Siz-PIAS really interesting new gene) zinc-finger domain characteristic of this family of proteins [16]. Genetic analysis shows that lack of Tna is lethal at post-embryonic stages [17], whereas expression analysis shows that it is down-regulated in the reproductive tissues of females after mating [18], it is induced at late stages of embryonic cellularization [19] and it is differentially expressed in embryonic head [20]. Functional analysis in Drosophila revealed that Tna interacts genetically with the SWI/SNF chromatin-remodelling complex [21] and is involved in the regulation of homoeotic gene expression during development. The lack of Tna produces a partial transformation of halteres to wings and other homoeotic transformations [21].

Another putative E3 ligase described in Drosophila is Su(var)2–10 (suppressor of variegation 2–10), also known as dPias, which is required to complete embryogenesis [22]. Position–effect variegation, a phenomenon well studied in, but not exclusive to, Drosophila causes the inactivation of genes by juxtaposition to heterochromatin regions, indicating a role for Su(var)2–10 in normal heterochromatic functions [23]. Su(var)2–10 is involved in the maintenance of the proper chromosomal structure and chromosomal inheritance [24,25]. Some combinations of su(var)210 mutations die as late larvae or early pupa and show melanotic tumours. Similarly to its vertebrate homologues, Su(var)2–10 is a negative regulator of the JAK (Janus kinase)/STAT pathway [26] and participates in the biological processes where this pathway is active, such as in the antiviral response [27], border cell migration during oogenesis [28] or blood cell and eye development, probably through the negative regulation of the transcription factor Stat92E [29].

Cellular roles for SUMOylation

During the last 10 years, a large number of proteins have been identified as SUMO substrates in vertebrates, as well as in Drosophila (Table 2). However, it is difficult to predict the impact that SUMOylation has on their biological roles. In fact, for some of the Smt3 target proteins, such as CaMKII (Ca2+/calmodulin-dependent protein kinase II), glutamyl-prolyl-tRNA synthetase, methionyl-tRNA synthetase, heat-shock proteins, Septin, Seven in absentia, Stumps or Tramtrack (Ttk), the role of SUMOylation remains unknown (Table 2). However, as discussed below, Smt3 conjugation to other factors links SUMOylation with various cellular processes such as cell survival and proliferation, nuclear import, intracellular trafficking, transcriptional regulation and maintenance of genomic and nuclear integrity.

Table 2
SUMOylation substrates in Drosophila

CAMK2D, Ca2+/calmodulin-dependent protein kinase IIδ; EPRS, glutamyl-prolyl-tRNA synthetase; MARS2, methionine-tRNA synthetase 2 precursor; NFKB1, nuclear factor κB1; PIK3AP1, phosphoinositide 3-kinase adaptor protein 1; SEPT2, septin 2; SIAH1, seven in absentia homologue 1; SOX1, SRY-box 1; TLE4, transducin-like enhancer of split 4 [E(sp1) homologue, Drosophila]; VGLL2, transcription cofactor vestigial-like protein 2; ZBTB, zinc finger and BTB (broad complex/Tramtrack/bric-a-brac) domain-containing protein.

SUMOylation substrates CG accession number Type of protein Homologues Interaction assay Role of SUMOylation Reference(s) 
Ca2+/calmodulin-dependent protein kinase II CG18069 Serine/threonine kinase CAMK2D In vivo Unknown [2
Centrosomal protein 190 kDa CG6384 Microtubule binding ZBTB In vivo Disrupts nuclear clustering [6
Dorsal CG6667 Transcription factor NFKB1 S2 cells/in vitro/in vivo Enhance the transcriptional activity; nuclear localization [33,52,55
Glutamyl-prolyl-tRNA synthetase CG5394 Aminoacyl-tRNA synthetase EPRS S2 cells Unknown [15
Groucho CG8384 Transcription cofactor TLE4 Yeast two-hybrid Unknown [4
Hsp23, Hsp26, Hsp27 CG4463, CG4183, CG4466 Heat-shock proteins Heat-shock protein 27 kDa S2 cells Unknown [11
Methionyl-tRNA synthetase CG31322 Aminoacyl-tRNA synthetase MARS2 S2 cells Unknown [15
Modifier of mdg4 CG32491 Chromatin binding ZBTB In vivo Disrupts nuclear clustering [6
Septin-1 CG1403 GTPase SEPT2 Yeast two-hybrid Unknown [7
Seven in absentia CG9949 E3 ubiquitin ligase SIAH1 Yeast two-hybrid Unknown [59
SoxNeuro CG18024 Transcription factor SOX1 S2 cells Transcriptional activity repression [42
Stat92E CG4257 Transcription factor STAT5B In vitro Transcriptional activity repression [29
Stumps CG31317 Adaptor protein PIK3AP1 Yeast two-hybrid Unknown [60
Tramtrack CG1856 Transcription factor ZBTB SL2 cells Unknown [3
Vestigial CG3830 Transcription co-factor VGLL2 S2 cells Enhances transcriptional activity [31
SUMOylation substrates CG accession number Type of protein Homologues Interaction assay Role of SUMOylation Reference(s) 
Ca2+/calmodulin-dependent protein kinase II CG18069 Serine/threonine kinase CAMK2D In vivo Unknown [2
Centrosomal protein 190 kDa CG6384 Microtubule binding ZBTB In vivo Disrupts nuclear clustering [6
Dorsal CG6667 Transcription factor NFKB1 S2 cells/in vitro/in vivo Enhance the transcriptional activity; nuclear localization [33,52,55
Glutamyl-prolyl-tRNA synthetase CG5394 Aminoacyl-tRNA synthetase EPRS S2 cells Unknown [15
Groucho CG8384 Transcription cofactor TLE4 Yeast two-hybrid Unknown [4
Hsp23, Hsp26, Hsp27 CG4463, CG4183, CG4466 Heat-shock proteins Heat-shock protein 27 kDa S2 cells Unknown [11
Methionyl-tRNA synthetase CG31322 Aminoacyl-tRNA synthetase MARS2 S2 cells Unknown [15
Modifier of mdg4 CG32491 Chromatin binding ZBTB In vivo Disrupts nuclear clustering [6
Septin-1 CG1403 GTPase SEPT2 Yeast two-hybrid Unknown [7
Seven in absentia CG9949 E3 ubiquitin ligase SIAH1 Yeast two-hybrid Unknown [59
SoxNeuro CG18024 Transcription factor SOX1 S2 cells Transcriptional activity repression [42
Stat92E CG4257 Transcription factor STAT5B In vitro Transcriptional activity repression [29
Stumps CG31317 Adaptor protein PIK3AP1 Yeast two-hybrid Unknown [60
Tramtrack CG1856 Transcription factor ZBTB SL2 cells Unknown [3
Vestigial CG3830 Transcription co-factor VGLL2 S2 cells Enhances transcriptional activity [31

Two lines of evidences associate SUMOylation with cell survival and proliferation. First, the SUMOylation components are expressed in proliferative tissues, such as the undifferentiated cells of imaginal discs or the gonads [5,1214]. Secondly, mutations in smt3 or lwr compromise cell proliferation and cell viability in imaginal discs and CNS [30,31].

The role of SUMOylation in cellular trafficking has been reported in various examples. Mutations in lwr impede the entrance of the embryonic morphogen Bicoid into the nucleus, and down-regulation of other components of the pathway causes accumulation of SUMOylated proteins in the cytoplasm [15,32]. Nuclear transport of the Rel transcription factor Dorsal (Dl) seems to be also influenced by SUMOylation, although further research is necessary to clarify the consequences of this modification [33,34]. smt3 and lwr are also related to intracellular trafficking and autophagy, interacting genetically with blue cheese, an autophagic-linked gene in which mutations lead to reduced lifespan, neuronal death and CNS degeneration [35].

SUMOylation has been associated with the enhancement of transcriptional activation or transcriptional repression. SUMOylation of Dl and the cofactor Vestigial (Vg) activate transcription, whereas the modification of SoxNeuro (SoxN) and Stat92E involves transcriptional activity repression (Table 2). In the case of SoxN, SUMOylation does not influence the subcellular localization of SoxN, although in other cases, it might affect the subcellular or nuclear distribution of the target transcription factor. A relationship between SUMO-dependent transcriptional regulation and subnuclear localization has been suggested, but the link between these two processes remains obscure.

A role for SUMOylation in chromatin regulation is reflected in the suppression of cytological defects shown in female meiotic mutations by lwr mutations. Lwr mediates the dissociation of heterochromatic regions at the end of the meiotic prophase I [36]. In addition, SUMOylation negatively regulates the activity of the gypsy chromatin insulator by inhibiting the long-range interaction of insulator-binding proteins [6,37]. Su(var)2–10 is also involved in chromosomal stabilization and maintenance [25]. This protein associates with telomeres and is closely associated with the nuclear periphery during interphase [25]. In its absence, telomere clustering is aberrant, as well as the association of telomeres with the nuclear lamina.

If SUMOylation is involved in this variety of cellular processes, it is not surprising that it has been involved in various developmental contexts, exemplified in the next section.

Developmental roles for SUMOylation in Drosophila

In Drosophila, the components of the pathway are expressed throughout development [24]. A number of processes seem to be influenced by SUMOylation, such as embryogenesis, wing morphogenesis and CNS development, as well as neurodegeneration and immune response.

Embryogenesis

Smt3 and Lwr are expressed at high levels during embryogenesis, and their absence produces embryonic lethality [3,7,11]. The analysis of mutations in lwr allowed elucidation of the biological role of the SUMOylation pathway in embryonic patterning. The mutation semushi, caused by an insertion in the 3′-UTR (untranslated region) regulatory region of lwr, results in late embryonic or first instar larvae lethality with defects in embryonic patterning. The anterior segmentation abnormalities in these homozygous mutant embryos are caused by defects in the nuclear import of Bicoid [32]. In addition, the defects in meiotic chromosome segregation founded in lwr mutations could also explain the relevance of this pathway during embryogenesis [36].

Wing morphogenesis

Vg, a selector gene necessary for wing morphogenesis, can be modified by Smt3 in S2 cells and interacts genetically with smt3, lwr and su(var)210 [31]. Expressed in the wing blade of the wing imaginal disc, Vg plays an essential role in the regulation of wing cell proliferation and differentiation [38]. Together with Scalloped, Vg forms a functional transcription factor that is required for wing development [39]. Interestingly, SUMOylation is required for the transcriptional activation of Vg during wing morphogenesis, although there are no data on how SUMOylation affects the Vg–Scalloped interaction [31].

Nervous system development and neurodegeneration

Some of the transcription factors modified by Smt3 are involved in the development of the CNS (Table 2). This is the case for SoxN, an SRY (sex-determining region Y) highmobility-group box transcription factor, expressed from the earlier stages of neurogenesis and involved in neuroblast formation [40,41]. Overexpression of a SoxN-SUMO-deficient mutated form produced several defects including fusion or absence of neural commissures and reduction or absence of longitudinal axon tracts that lead to disruption of CNS development and embryonic lethality. Therefore the SUMO-mediated transcriptional repression of SoxN seems to be important for proper CNS development [42].

The zinc-finger protein Ttk, which is another in vivo substrate of Smt3 [3], represses neural stem cell-specific genes and maintain glial differentiation in embryonic CNS [43], acting as a repressor of neural fate determination in the peripheral nervous system [44]. As Smt3 is expressed at high levels in sensory organ cells such as sensory bristles, it could play a role in the fate determination in the peripheral nervous system. However, the biological role of Smt3 conjugation of Ttk in neuronal differentiation repression is unclear [3].

The components of SUMOylation machinery are highly expressed in neurons. The reported Smt3 conjugation in vivo of one isoform of the neuronal CaMKII, with important roles in synaptic plasticity, learning and memory, implicates SUMOylation in the regulation of differentiated neurons [2]. In fact, the overexpression of wild-type Uba2 or a putative Uba2 dominant-negative mutant in the nervous system leads to pupal lethality. This suggests the requirement of a normal SUMOylation pathway for Drosophila CNS differentiation [2].

SUMO has been implicated in several neurodegenerative diseases (reviewed in [45]), based on co-localizing SUMO with neuronal inclusions associated with some of these diseases. In addition, several proteins implicated in these disorders such as huntingtin (HTT), Ataxin-1, tau and α-synclein are modified by SUMO. Drosophila, as a model for human diseases, has been used to investigate the role of SUMOylation in neurodegenerative pathologies [46,47]. The best examples are HD (Huntington's disease) and SBMA (spinal and bulbar muscular atrophy), both included in the group of human polyglutamine neurodegenerative diseases associated with the expansion of CAG triplet repeats. Studies in Drosophila showed the SUMOylation of the N-terminal fragment of human HTT, the pathogenic protein accumulated in HD [48]. Although SUMOylation of HTT reduced aggregate formation, it enhanced the ability of HTT to induce neurodegeneration, probably by increasing the levels of toxic soluble oligomers. The mechanism of SUMO action in this neurodegenerative disorder is not completely clear. HTT can also be ubiquitinated, thus SUMOylation could antagonize the ubiquitin–proteasome degradation pathway or both post-translational modification systems could co-ordinately co-operate and contribute to HD pathogenesis. In addition, SUMO modification increased the transcriptional repression mediated by HTT [48].

SBMA, caused by the expansion of a polyglutamine repeat within the androgen receptor protein [49], is another neurodegenerative disease modelled in Drosophila [50,51]. There, the overexpression of a mutated form of Uba2 enhanced neurodegeneration, showing again the important role of SUMOylation in the modulation of polyglutamine pathogenesis [50].

Immune response

Several studies have also implicated SUMOylation in the immune response. As mentioned above, the transcription factor Dl, with a role in innate immunity, is an Smt3 target protein [33,52]. In addition, the Smt3 conjugation machinery seems to be required for lipopolysaccharide-induced expression of the antimicrobial peptides cecropinA1 and drosomycin and for phagocytosis and intracellular growth of pathogens [33,53,54]. Mutations in lwr lead to overproliferation of haemocytes and differentiation defects. Lwr seems to play an important role in the regulation of larval haemopoiesis by the negative regulation of the Rel-related proteins Dl and Dorsal-related immunity factor [34,55,56]. However, further studies are required, as divergent results have been obtained related to the Lwr-mediated nuclear localization of Dl and Dorsal-related immunity factor [33,55].

Concluding remarks

A growing body of evidence relates SUMOylation to crucial cellular and developmental processes. In development, where transcription, translation and cellular localization are critically regulated, the versatility and reversibility of SUMOylation makes it a plausible candidate to participate in ‘fine-tuning’ regulation of signalling pathways and downstream effectors. We predict that the genetic advantages of Drosophila will allow the study of SUMOylation to progress rapidly in the coming years, and that the fruitfly model will provide crucial correlations between biochemical and cellular observations and complex organismal phenotypes.

Note added in proof (received 4 August 2008)

While this article was in the press, our paper describing the role of Smt3 during metamorphasis was published, representing a new function for SUMOylation during development [61].

Third Intracellular Proteolysis Meeting: A joint Biochemical Society and INPROTEOLYS Network Focused Meeting held at Auditorio de Tenerife, Santa Cruz de Tenerife, Canary Islands, Spain, 5–7 March 2008. Organized and Edited by Rosa Farràs (Centro de Investigación Príncipe Felipe, Valencia, Spain), Gemma Marfany (Barcelona, Spain), Manuel Rodríguez (CICbioGUNE, Derio, Spain), Eduardo Salido (La Laguna, Tenerife, Spain) and Dimitris Xirodimas (Dundee, U.K.).

Abbreviations

     
  • CaMKII

    Ca2+/calmodulin-dependent protein kinase II

  •  
  • CNS

    central nervous system

  •  
  • Dl

    Dorsal

  •  
  • HTT

    huntingtin

  •  
  • HD

    Huntington's disease

  •  
  • Lwr

    Lesswright

  •  
  • SBMA

    spinal and bulbar muscular atrophy

  •  
  • SoxN

    SoxNeuro

  •  
  • STAT

    signal transducer and activator of transcription

  •  
  • PIAS

    protein inhibitor of activated STAT

  •  
  • Su(var)2–10

    suppressor of variegation 2–10

  •  
  • SUMO

    small ubiquitin-related modifier

  •  
  • Tna

    Tonalli

  •  
  • Ttk

    Tramtrack

  •  
  • Vg

    Vestigial

We thank J.D. Sutherland for the critical reading of the manuscript. We acknowledge the Spanish Ministry of Science and Education (BFU2005-00257), the Department of Industry, Tourism and Trade of the Government of the Basque Country Autonomous Community (Etortek Research Programs 2005/2006) and the Innovation Technology Department of the Bizkaia County. R.B. belongs to the Ramón y Cajal programme.

References

References
1
Huang
H.W.
Tsoi
S.C.
Sun
Y.H.
Li
S.S.
Identification and characterization of the SMT3 cDNA and gene encoding ubiquitin-like protein from Drosophila melanogaster
Biochem. Mol. Biol. Int.
1998
, vol. 
46
 (pg. 
775
-
785
)
2
Long
X.
Griffith
L.C.
Identification and characterization of a SUMO-1 conjugation system that modifies neuronal calcium/calmodulin-dependent protein kinase II in Drosophila melanogaster
J. Biol. Chem.
2000
, vol. 
275
 (pg. 
40765
-
40776
)
3
Lehembre
F.
Badenhorst
P.
Muller
S.
Travers
A.
Schweisguth
F.
Dejean
A.
Covalent modification of the transcriptional repressor Tramtrack by the ubiquitin-related protein Smt3 in Drosophila flies
Mol. Cell. Biol.
2000
, vol. 
20
 (pg. 
1072
-
1082
)
4
Ohsako
S.
Takamatsu
Y.
Identification and characterization of a Drosophila homologue of the yeast UBC9 and hus5 genes
J. Biochem. (Tokyo)
1999
, vol. 
125
 (pg. 
230
-
235
)
5
Shigenobu
S.
Kitadate
Y.
Noda
C.
Kobayashi
S.
Molecular characterization of embryonic gonads by gene expression profiling in Drosophila melanogaster
Proc. Natl. Acad. Sci. U.S.A.
2006
, vol. 
103
 (pg. 
13728
-
13733
)
6
Capelson
M.
Corces
V.G.
SUMO conjugation attenuates the activity of the gypsy chromatin insulator
EMBO J.
2006
, vol. 
25
 (pg. 
1906
-
1914
)
7
Shih
H.P.
Hales
K.G.
Pringle
J.R.
Peifer
M.
Identification of septin-interacting proteins and characterization of the Smt3/SUMO-conjugation system in Drosophila
J. Cell Sci.
2002
, vol. 
115
 (pg. 
1259
-
1271
)
8
Altenhein
B.
Becker
A.
Busold
C.
Beckmann
B.
Hoheisel
J.D.
Technau
G.M.
Expression profiling of glial genes during Drosophila embryogenesis
Dev. Biol.
2006
, vol. 
296
 (pg. 
545
-
560
)
9
Donaghue
C.
Bates
H.
Cotterill
S.
Identification and characterisation of the Drosophila homologue of the yeast Uba2 gene
Biochim. Biophys. Acta
2001
, vol. 
1518
 (pg. 
210
-
214
)
10
Gonzalez-Aguero
M.
Zuniga
A.
Pottstock
H.
Del Pozo
T.
Gonzalez
M.
Cambiazo
V.
Identification of genes expressed during Drosophila melanogaster gastrulation by using subtractive hybridization
Gene
2005
, vol. 
345
 (pg. 
213
-
224
)
11
Joanisse
D.R.
Inaguma
Y.
Tanguay
R.M.
Cloning and developmental expression of a nuclear ubiquitin-conjugating enzyme (DmUbc9) that interacts with small heat shock proteins in Drosophila melanogaster
Biochem. Biophys. Res. Commun.
1998
, vol. 
244
 (pg. 
102
-
109
)
12
Mukai
M.
Kitadate
Y.
Arita
K.
Shigenobu
S.
Kobayashi
S.
Expression of meiotic genes in the germline progenitors of Drosophila embryos
Gene Expression Patterns
2006
, vol. 
6
 (pg. 
256
-
266
)
13
Proschel
M.
Zhang
Z.
Parsch
J.
Widespread adaptive evolution of Drosophila genes with sex-biased expression
Genetics
2006
, vol. 
174
 (pg. 
893
-
900
)
14
Jasper
H.
Benes
V.
Atzberger
A.
Sauer
S.
Ansorge
W.
Bohmann
D.
A genomic switch at the transition from cell proliferation to terminal differentiation in the Drosophila eye
Dev. Cell
2002
, vol. 
3
 (pg. 
511
-
521
)
15
Smith
M.
Bhaskar
V.
Fernandez
J.
Courey
A.J.
Drosophila Ulp1, a nuclear pore-associated SUMO protease, prevents accumulation of cytoplasmic SUMO conjugates
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
43805
-
43814
)
16
Rodriguez-Magadan
H.
Merino
E.
Schnabel
D.
Ramirez
L.
Lomeli
H.
Spatial and temporal expression of Zimp7 and Zimp10 PIAS-like proteins in the developing mouse embryo
Gene Expression Patterns
2008
, vol. 
8
 (pg. 
206
-
213
)
17
Deak
P.
Omar
M.M.
Saunders
R.D.
Pal
M.
Komonyi
O.
Szidonya
J.
Maroy
P.
Zhang
Y.
Ashburner
M.
Benos
P.
, et al. 
P-element insertion alleles of essential genes on the third chromosome of Drosophila melanogaster: correlation of physical and cytogenetic maps in chromosomal region 86E-87F
Genetics
1997
, vol. 
147
 (pg. 
1697
-
1722
)
18
Mack
P.D.
Kapelnikov
A.
Heifetz
Y.
Bender
M.
Mating-responsive genes in reproductive tissues of female Drosophila melanogaster
Proc. Natl. Acad. Sci. U.S.A.
2006
, vol. 
103
 (pg. 
10358
-
10363
)
19
Pilot
F.
Philippe
J.M.
Lemmers
C.
Chauvin
J.P.
Lecuit
T.
Developmental control of nuclear morphogenesis and anchoring by charleston, identified in a functional genomic screen of Drosophila cellularisation
Development
2006
, vol. 
133
 (pg. 
711
-
723
)
20
Brody
T.
Stivers
C.
Nagle
J.
Odenwald
W.F.
Identification of novel Drosophila neural precursor genes using a differential embryonic head cDNA screen
Mech. Dev.
2002
, vol. 
113
 (pg. 
41
-
59
)
21
Gutierrez
L.
Zurita
M.
Kennison
J.A.
Vazquez
M.
The Drosophila trithorax group gene tonalli (tna) interacts genetically with the Brahma remodeling complex and encodes an SP-RING finger protein
Development
2003
, vol. 
130
 (pg. 
343
-
354
)
22
Mohr
S.E.
Boswell
R.E.
Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster
Gene
1999
, vol. 
229
 (pg. 
109
-
116
)
23
Reuter
G.
Wolff
I.
Isolation of dominant suppressor mutations for position-effect variegation in Drosophila melanogaster
Mol. Gen. Genet.
1981
, vol. 
182
 (pg. 
516
-
519
)
24
Le
H.D.
Donaldson
K.M.
Cook
K.R.
Karpen
G.H.
A high proportion of genes involved in position effect variegation also affect chromosome inheritance
Chromosoma
2004
, vol. 
112
 (pg. 
269
-
276
)
25
Hari
K.L.
Cook
K.R.
Karpen
G.H.
The Drosophila Su(var)2–10 locus regulates chromosome structure and function and encodes a member of the PIAS protein family
Genes Dev.
2001
, vol. 
15
 (pg. 
1334
-
1348
)
26
Hombria
J.C.
Brown
S.
The fertile field of Drosophila Jak/STAT signalling
Curr. Biol.
2002
, vol. 
12
 (pg. 
R569
-
R575
)
27
Dostert
C.
Jouanguy
E.
Irving
P.
Troxler
L.
Galiana-Arnoux
D.
Hetru
C.
Hoffmann
J.A.
Imler
J.L.
The Jak-STAT signaling pathway is required but not sufficient for the antiviral response of Drosophila
Nat. Immunol.
2005
, vol. 
6
 (pg. 
946
-
953
)
28
Ghiglione
C.
Devergne
O.
Georgenthum
E.
Carballes
F.
Medioni
C.
Cerezo
D.
Noselli
S.
The Drosophila cytokine receptor Domeless controls border cell migration and epithelial polarization during oogenesis
Development
2002
, vol. 
129
 (pg. 
5437
-
5447
)
29
Betz
A.
Lampen
N.
Martinek
S.
Young
M.W.
Darnell
J.E.
Jr
A Drosophila PIAS homologue negatively regulates Stat92E
Proc. Natl. Acad. Sci. U.S.A.
2001
, vol. 
98
 (pg. 
9563
-
9568
)
30
Watts
R.J.
Hoopfer
E.D.
Luo
L.
Axon pruning during Drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin–proteasome system
Neuron
2003
, vol. 
38
 (pg. 
871
-
885
)
31
Takanaka
Y.
Courey
A.J.
SUMO enhances Vestigial function during wing morphogenesis
Mech. Dev.
2005
, vol. 
122
 (pg. 
1130
-
1137
)
32
Epps
J.L.
Tanda
S.
The Drosophila semushi mutation blocks nuclear import of Bicoid during embryogenesis
Curr. Biol.
1998
, vol. 
8
 (pg. 
1277
-
1280
)
33
Bhaskar
V.
Smith
M.
Courey
A.J.
Conjugation of Smt3 to Dorsal may potentiate the Drosophila immune response
Mol. Cell. Biol.
2002
, vol. 
22
 (pg. 
492
-
504
)
34
Huang
L.
Ohsako
S.
Tanda
S.
The lesswright mutation activates Rel-related proteins, leading to overproduction of larval hemocytes in Drosophila melanogaster
Dev. Biol.
2005
, vol. 
280
 (pg. 
407
-
420
)
35
Simonsen
A.
Cumming
R.C.
Lindmo
K.
Galaviz
V.
Cheng
S.
Rusten
T.E.
Finley
K.D.
Genetic modifiers of the Drosophila blue cheese gene link defects in lysosomal transport with decreased lifespan and altered ubiquitinated protein profiles
Genetics
2007
, vol. 
176
 (pg. 
1283
-
1297
)
36
Apionishev
S.
Malhotra
D.
Raghavachari
S.
Tanda
S.
Rasooly
R.S.
The Drosophila UBC9 homologue Lesswright mediates the disjunction of homologues in meiosis I
Genes Cells
2001
, vol. 
6
 (pg. 
215
-
224
)
37
Krupp
J.J.
Yaich
L.E.
Wessells
R.J.
Bodmer
R.
Identification of genetic loci that interact with cut during Drosophila wing-margin development
Genetics
2005
, vol. 
170
 (pg. 
1775
-
1795
)
38
Williams
J.A.
Bell
J.B.
Carroll
S.B.
Control of Drosophila wing and haltere development by the nuclear vestigial gene product
Genes Dev.
1991
, vol. 
5
 (pg. 
2481
-
2495
)
39
Halder
G.
Polaczyk
P.
Kraus
M.E.
Hudson
A.
Kim
J.
Laughon
A.
Carroll
S.
The Vestigial and Scalloped proteins act together to directly regulate wing-specific gene expression in Drosophila
Genes Dev.
1998
, vol. 
12
 (pg. 
3900
-
3909
)
40
Cremazy
F.
Berta
P.
Girard
F.
Sox neuro, a new Drosophila Sox gene expressed in the developing central nervous system
Mech. Dev.
2000
, vol. 
93
 (pg. 
215
-
219
)
41
Buescher
M.
Hing
F.S.
Chia
W.
Formation of neuroblasts in the embryonic central nervous system of Drosophila melanogaster is controlled by SoxNeuro
Development
2002
, vol. 
129
 (pg. 
4193
-
4203
)
42
Savare
J.
Bonneaud
N.
Girard
F.
SUMO represses transcriptional activity of the Drosophila SoxNeuro and human Sox3 central nervous system-specific transcription factors
Mol. Biol. Cell
2005
, vol. 
16
 (pg. 
2660
-
2669
)
43
Badenhorst
P.
Finch
J.T.
Travers
A.A.
Tramtrack co-operates to prevent inappropriate neural development in Drosophila
Mech. Dev.
2002
, vol. 
117
 (pg. 
87
-
101
)
44
Guo
M.
Jan
L.Y.
Jan
Y.N.
Control of daughter cell fates during asymmetric division: interaction of Numb and Notch
Neuron
1996
, vol. 
17
 (pg. 
27
-
41
)
45
Dorval
V.
Fraser
P.E.
SUMO on the road to neurodegeneration
Biochim. Biophys. Acta
2007
, vol. 
1773
 (pg. 
694
-
706
)
46
Celotto
A.M.
Palladino
M.J.
Drosophila: a “model” model system to study neurodegeneration
Mol. Interv.
2005
, vol. 
5
 (pg. 
292
-
303
)
47
Marsh
J.L.
Thompson
L.M.
Drosophila in the study of neurodegenerative disease
Neuron
2006
, vol. 
52
 (pg. 
169
-
178
)
48
Steffan
J.S.
Agrawal
N.
Pallos
J.
Rockabrand
E.
Trotman
L.C.
Slepko
N.
Illes
K.
Lukacsovich
T.
Zhu
Y.Z.
Cattaneo
E.
, et al. 
SUMO modification of Huntingtin and Huntington's disease pathology
Science
2004
, vol. 
304
 (pg. 
100
-
104
)
49
La Spada
A.R.
Wilson
E.M.
Lubahn
D.B.
Harding
A.E.
Fischbeck
K.H.
Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy
Nature
1991
, vol. 
352
 (pg. 
77
-
79
)
50
Chan
H.Y.
Warrick
J.M.
Andriola
I.
Merry
D.
Bonini
N.M.
Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila
Hum. Mol. Genet.
2002
, vol. 
11
 (pg. 
2895
-
2904
)
51
Takeyama
K.
Ito
S.
Yamamoto
A.
Tanimoto
H.
Furutani
T.
Kanuka
H.
Miura
M.
Tabata
T.
Kato
S.
Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila
Neuron
2002
, vol. 
35
 (pg. 
855
-
864
)
52
Bhaskar
V.
Valentine
S.A.
Courey
A.J.
A functional interaction between Dorsal and components of the Smt3 conjugation machinery
J. Biol. Chem.
2000
, vol. 
275
 (pg. 
4033
-
4040
)
53
Stroschein-Stevenson
S.L.
Foley
E.
O'Farrell
P.H.
Johnson
A.D.
Identification of Drosophila gene products required for phagocytosis of Candida albicans
PLoS Biol.
2006
, vol. 
4
 pg. 
e4
 
54
Cheng
L.W.
Viala
J.P.
Stuurman
N.
Wiedemann
U.
Vale
R.D.
Portnoy
D.A.
Use of RNA interference in Drosophila S2 cells to identify host pathways controlling compartmentalization of an intracellular pathogen
Proc. Natl. Acad. Sci. U.S.A.
2005
, vol. 
102
 (pg. 
13646
-
13651
)
55
Chiu
H.
Ring
B.C.
Sorrentino
R.P.
Kalamarz
M.
Garza
D.
Govind
S.
dUbc9 negatively regulates the Toll–NF-κB pathways in larval hematopoiesis and drosomycin activation in Drosophila
Dev. Biol.
2005
, vol. 
288
 (pg. 
60
-
72
)
56
Milchanowski
A.B.
Henkenius
A.L.
Narayanan
M.
Hartenstein
V.
Banerjee
U.
Identification and characterization of genes involved in embryonic crystal cell formation during Drosophila hematopoiesis
Genetics
2004
, vol. 
168
 (pg. 
325
-
339
)
57
Schnorr
J.D.
Holdcraft
R.
Chevalier
B.
Berg
C.A.
Ras1 interacts with multiple new signaling and cytoskeletal loci in Drosophila eggshell patterning and morphogenesis
Genetics
2001
, vol. 
159
 (pg. 
609
-
622
)
58
Muller
P.
Kuttenkeuler
D.
Gesellchen
V.
Zeidler
M.P.
Boutros
M.
Identification of JAK/STAT signalling components by genome-wide RNA interference
Nature
2005
, vol. 
436
 (pg. 
871
-
875
)
59
Hu
G.
Zhang
S.
Vidal
M.
Baer
J.L.
Xu
T.
Fearon
E.R.
Mammalian homologs of Seven in absentia regulate DCC via the ubiquitin-proteasome pathway
Genes Dev.
1997
, vol. 
11
 (pg. 
2701
-
2714
)
60
Battersby
A.
Csiszar
A.
Leptin
M.
Wilson
R.
Isolation of proteins that interact with the signal transduction molecule Dof and identification of a functional domain conserved between Dof and vertebrate BCAP
J. Mol. Biol.
2003
, vol. 
329
 (pg. 
479
-
493
)
61
Talamillo
A.
Sánchez
J.
Cantera
R.
Pérez
C.
Martin
D.
Caninero
E.
Barrio
R.
Smt3 is required for Drosophila melanogaster metamorphosis
Development
2008
, vol. 
135
 (pg. 
1659
-
1668
)