The RelA (p65) NF-κB (nuclear factor κB) subunit contains an extremely active C-terminal transcriptional activation domain, required for its cellular function. In the present article, we review our knowledge of this domain, its modifications and its known interacting proteins. Moreover, we discuss how analysis of its evolutionary conservation reveals distinct subdomains and conserved residues that might give insights into its regulation and function.

Introduction

NF-κB (nuclear factor κB) is a collective term for a family of transcription factors with a highly diverse spectrum of modulating stimuli and an ever-increasing array of genetic targets [1,2]. They are evolutionarily and structurally conserved and have representative members in a wide range of species. It has been suggested that the first NF-κB transcription factor originated at the dawn of the metazoan lineage [3,4]. The five members of the mammalian NF-κB family are RelA (p65), RelB, cRel, p105/p50 (NF-κB1) and p100/p52 (NF-κB2 or lyt10), which are capable of forming a large number of homo- and hetero-dimeric complexes. The N-terminus of this protein family contains a 300-amino-acid highly conserved RHD (Rel homology domain), which mediates DNA binding, dimerization and nuclear localization, and enables association with one of the members of the IκB (inhibitor of NF-κB) protein family, IκBα, IκBβ or IκBϵ. RelA, RelB and c-Rel contain non-homologous TADs (transactivation domains) in their C-termini which enables them to recruit co-transcriptional regulators and basal transcriptional machinery to their gene targets. In nearly all unstimulated cells, NF-κB dimers are retained in their inactive cytoplasmic form through binding to a member of the IκB family. Activation of the NF-κB family typically occurs following the activation of the IKK (IκB kinase) signalosome, resulting in the phosphorylation and subsequent proteolytic degradation of the inhibitory IκB molecule. This liberates NF-κB dimers, allowing nuclear translocation and transcriptional regulation of target genes [5]. Aberrant activation of NF-κB proteins has been implicated in many different inflammatory diseases [6]. NF-κB has also been shown to play a critical role in determining the growth and survival of cancer cells and functions as a link between chronic inflammatory conditions and tumour development [7,8]. NF-κB transcription factors have traditionally been thought of as anti-apoptotic and tumour-promoting. However, pro-apoptotic roles for NF-κB are increasingly being described [9]. Moreover, in some disease models, IKK/NF-κB signalling has been shown to have a tumour-suppressive effect [2,9]. Determining the molecular mechanisms behind these differing roles of NF-κB should enable more effective therapeutic treatments to be utilized when treating those diseases where NF-κB has a causative or preventative role.

Despite the intense research into NF-κB function, there is still a large number of questions remaining about the molecular mechanisms that define NF-κB family member transcriptional activity. Regulation of nuclear translocation, dimer composition, association with other regulatory proteins and many post-translational modifications have been identified and these can all contribute to the specificity required for appropriate, context-dependent, gene regulation by NF-κB. However, it can be anticipated that many further regulatory events remain to be clearly defined. RelA is the most abundantly studied member of this protein family, and the present article will review our current knowledge of its C-terminal TAD, its division into subdomains, the features within each domain that allow for transcription to be regulated and the proteins that have been shown to interact with it.

The RelA protein

RelA is a 551-amino-acid ubiquitously expressed protein, composed of an N-terminal RHD and a C-terminal TAD. Although the RHD shows a high degree of homology with other NF-κB family members and across species, the TAD diverges to a greater extent, especially when comparing between other TAD-containing family members. Across species, however, regions of higher homology are evident (Figure 1). The TAD is traditionally divided into two distinct transactivation domains, TA1 and TA2, which have been shown to be necessary for the transcriptional activation of RelA [10]. TA1 is located in the C-terminal portion of the TAD (residues 521–551) and TA2 is in the preceding 90 amino acids (residues 428–521). The activity of the RelA TAD can be regulated by phosphorylation, and a number of key sites have been identified (see below). However, it is interesting to note that the entire TAD is devoid of lysine residues, implying that direct regulation of this domain is independent of lysine modifications such as acetylation, methylation, SUMOylation, ubiquitination and NEDDylation.

Schematic diagram showing structure of the RelA NF-κB subunit and the homology between the RelA transcriptional activation domains of human, mouse, rat, Xenopus and chicken

Figure 1
Schematic diagram showing structure of the RelA NF-κB subunit and the homology between the RelA transcriptional activation domains of human, mouse, rat, Xenopus and chicken

Conserved amino acids are shown in bold, and blocks of homology are highlighted. Conserved phenylalanine residues shown to be important for transactivation domain function [12] are underlined. The human sequence is from amino acids 428 to 551. | represents a conserved potential serine/threonine/tyrosine phosphorylation site. Sites reported to be phosphorylated are indicated with the amino acid number. *Glu→Asp mutation found in multiple myeloma patients [20].

Figure 1
Schematic diagram showing structure of the RelA NF-κB subunit and the homology between the RelA transcriptional activation domains of human, mouse, rat, Xenopus and chicken

Conserved amino acids are shown in bold, and blocks of homology are highlighted. Conserved phenylalanine residues shown to be important for transactivation domain function [12] are underlined. The human sequence is from amino acids 428 to 551. | represents a conserved potential serine/threonine/tyrosine phosphorylation site. Sites reported to be phosphorylated are indicated with the amino acid number. *Glu→Asp mutation found in multiple myeloma patients [20].

TA1 (residues 521–551)

TA1 was originally identified through its ability to restore up to 95% of the transactivation potential of full-length RelA, with the exact amount dependent on the cell type used [10]. An acidic activation domain, conserved phenylalanine residues and the formation of a α-helical conformation were found to be potential contributors to the transactivation activity [11,12]. There is also a potential LXXLL motif over amino acids 523–528; however, this has not been investigated in the literature (LXXLL motifs are frequently found in transcription factors and mediate protein–protein interactions [13]). Two phosphorylation sites have been identified within this domain. Phosphorylation of Ser529 by protein kinase CKII has been shown to increase transactivation. Ser536 can be phosphorylated by IKKα, IKKβ, IKKϵ, NAK (NF-κB-activating kinase) and RSK1 (ribosomal S6 kinase 1), having effects on both nuclear translocation stability and transactivation [14]. There are five other possible phosphorylatable residues within TA1, which could mediate further regulation of TA1 activity.

TA2 (residues 428–521)

TA2 was originally shown to mediate up to 30% of full-length RelA transcriptional activity [10]. Later studies have isolated further the subdomains within TA2 which can mediate transcriptional activation [10,15,16]. On closer analysis, it is possible to divide TA2 further into three conserved blocks, which show a greater degree of homology than the surrounding regions. We propose to name these CR (conserved region) 1, 2 and 3. We suggest that these conserved motifs are likely to represent protein–protein interaction domains whose function can be regulated by conserved phosphorylation sites.

CR1

CR1 spans residues 435–455. Dephosphorylation at Thr435 within this region by PP (protein phosphatase) 4 was shown to enhance RelA-mediated activation by the chemotherapeutic drug cisplatin, implying that phosphorylation at Thr435 has a negative effect on transcriptional activation [14]. A nuclear export signal has also been identified at residues 436–445 [17], which could contribute to nuclear to cytoplasmic shuttling of RelA-containing complexes. It has also been suggested that this region may contain a mini-leucine zipper (Leu435, Leu443 and Leu450), which, when removed, reduces transactivation [10]. Subsequently, it was found that mutation of Leu443 alone was shown to curtail transactivation [18]. There are also two potential LXXLL motifs within the region (over residues 436–441 and 450–454), which could potentially mediate interactions with co-transcriptional regulators; however, the functional significance of these potential motifs has not yet been elucidated. There is also one other phosphorylatable residue within CR1, Ser437, which could mediate further regulation of this region.

CR2

CR2 spans residues 462–479. This region contains two heptapeptide repeats (residues 464–472 and 472–480) within a TA1-like sequence, which spans residues 458–483. When multimerized, these residues were sufficient to activate transcription [19]. Phosphorylation at Ser468 within this region by GSK3β (glycogen synthase kinase 3β), IKKϵ and IKKβ has been reported, resulting in both an inhibitory and activating effect on transactivation [14]. There are also two other phosphorylatable residues within CR2, Thr464 and Ser472, which could mediate further regulation of activity by this region.

CR3

CR3 spans residues 491–505. The only published cancer-associated missense mutation found in RelA is located within this region: a multiple myeloma patient was found to have an E495D mutation, resulting in a form of RelA with altered DNA-binding and transactivation properties [20]. Phosphorylation at Thr505 by Chk1 (checkpoint kinase 1) has been reported to have an inhibitory effect on transactivation [21,22]. There are also two other phosphorylatable residues within CR3, Tyr496 and Thr501, which could mediate further regulation of this region.

Transactivation domain-interacting proteins

The transactivation ability of RelA is mediated by interactions of the TAD with co-transcriptional regulators and the basal transcription machinery. Surprisingly, only 27 proteins have been shown to interact directly with the RelA TAD (Table 1), although a further 72 proteins have been shown to interact with full-length RelA, and it would be expected that a proportion of them would interact with the TAD (see Supplementary Table S1 at http://www.biochemsoctrans.org/bst/036/bst0360603add.htm). In addition, 28 proteins have been found to interact with the RHD and seven proteins with the central region of RelA.

Table 1
RelA C-terminal TAD-interacting proteins

The Table represents a compilation of proteins known to interact with the RelA TAD, together with a summary of the evidence for these interactions and their functional consequences. In vitro and cell-based pull-downs involve overexpression of one or both proteins. Co-IP is where interaction has been demonstrated via co-immunoprecipitation of endogenous proteins. Data were collected via literature searches and the use of information listed at http://www.nf-kb.org. GST, glutathione transferase.

Interacting protein Definition Interaction demonstrated through Functional effect Reference 
TBP TATA-box-binding protein In vitro pull-down Enhances activity [24
p300  In vitro pull-down Cell-based pull-down Co-IP Mammalian two-hybrid assay Enhances activity [25,26
CBP CREB (cAMP-response-element-binding protein)-binding protein    
AO7 RING (really interesting new gene) finger protein In vitro pull-down Cell-based pull-down Enhances activity [27
TLS Translocated in liposarcoma Yeast two-hybrid In vitro pull-down Cell-based pull-down Enhances activity [28
RNA helicase A  Yeast two-hybrid In vitro pull-down Cell-based pull-down Enhances activity [29
ARC complex Activator-recruited cofactor complex GST–RelA TAD pull-down Enhances activity [30
TAFII31 TATA-box-binding-protein-associated factor 31 In vitro pull-down Enhances activity [23
TAFII250 TATA-box-binding-protein-associated factor 250 In vitro pull-down Decreases basal activity and enhances induced activity [31
TAFII80 TATA-box-binding-protein-associated factor 80 In vitro pull-down Decreases basal activity enhances induced activity [31
TAFII28 TATA-box-binding-protein-associated factor 28 In vitro pull-down Decreases basal activity enhances induced activity [31
MYBBP1a Myb-binding protein 1a In vitro pull-down Decreases activity [32,33
AES N-terminal enhancer of split Yeast two-hybrid In vitro pull-down Cell-based pull-down Decreases activity [34
DEK  Yeast two-hybrid Cell-based pull-down Co-IP Decreases activity [35
IEX-1 Immediate-early response gene X1 In vitro pull-down Co-IP Decreases activity [36
Oct1  In vitro pull-down Co-IP Decreases activity [37
SMRT Silencing mediator of retinoid and thyroid hormone receptors In vitro pull-down Yeast two-hybrid Decreases activity [38
PIAS1 Protein inhibitor of activated STAT (signal transducer and activator of transcription) 1 Cell-based pull-down Inhibits DNA binding [39
PP2A Protein phosphatase 2A In vitro pull-down Co-IP Dephosphorylates RelA [40
p53  In vitro pull-down Co-IP Inhibits p53 activity [41
TFIIB Transcription factor IIB In vitro pull-down In vivo yeast None observed [24
DNA-PKcs DNA-dependent protein kinase catalytic subunit GST–RelA TAD pull-down Not investigated [32
DRIM Down-regulated in metastasis GST–RelA TAD pull-down Not investigated [32
hGCN1L1 Human general control of amino acid synthesis 1-like 1 GST–RelA TAD pull-down Not investigated [32
IQGAP3 IQ motif-containing GTPase-activating protein 3 GST–RelA TAD pull-down Not investigated [32
TRRAP Transformation/transcription domain-associated protein GST–RelA TAD pull-down Not investigated [32
ATR Ataxia telangiectasia mutated- and Rad3-related GST–RelA TAD pull-down Not investigated [32
Interacting protein Definition Interaction demonstrated through Functional effect Reference 
TBP TATA-box-binding protein In vitro pull-down Enhances activity [24
p300  In vitro pull-down Cell-based pull-down Co-IP Mammalian two-hybrid assay Enhances activity [25,26
CBP CREB (cAMP-response-element-binding protein)-binding protein    
AO7 RING (really interesting new gene) finger protein In vitro pull-down Cell-based pull-down Enhances activity [27
TLS Translocated in liposarcoma Yeast two-hybrid In vitro pull-down Cell-based pull-down Enhances activity [28
RNA helicase A  Yeast two-hybrid In vitro pull-down Cell-based pull-down Enhances activity [29
ARC complex Activator-recruited cofactor complex GST–RelA TAD pull-down Enhances activity [30
TAFII31 TATA-box-binding-protein-associated factor 31 In vitro pull-down Enhances activity [23
TAFII250 TATA-box-binding-protein-associated factor 250 In vitro pull-down Decreases basal activity and enhances induced activity [31
TAFII80 TATA-box-binding-protein-associated factor 80 In vitro pull-down Decreases basal activity enhances induced activity [31
TAFII28 TATA-box-binding-protein-associated factor 28 In vitro pull-down Decreases basal activity enhances induced activity [31
MYBBP1a Myb-binding protein 1a In vitro pull-down Decreases activity [32,33
AES N-terminal enhancer of split Yeast two-hybrid In vitro pull-down Cell-based pull-down Decreases activity [34
DEK  Yeast two-hybrid Cell-based pull-down Co-IP Decreases activity [35
IEX-1 Immediate-early response gene X1 In vitro pull-down Co-IP Decreases activity [36
Oct1  In vitro pull-down Co-IP Decreases activity [37
SMRT Silencing mediator of retinoid and thyroid hormone receptors In vitro pull-down Yeast two-hybrid Decreases activity [38
PIAS1 Protein inhibitor of activated STAT (signal transducer and activator of transcription) 1 Cell-based pull-down Inhibits DNA binding [39
PP2A Protein phosphatase 2A In vitro pull-down Co-IP Dephosphorylates RelA [40
p53  In vitro pull-down Co-IP Inhibits p53 activity [41
TFIIB Transcription factor IIB In vitro pull-down In vivo yeast None observed [24
DNA-PKcs DNA-dependent protein kinase catalytic subunit GST–RelA TAD pull-down Not investigated [32
DRIM Down-regulated in metastasis GST–RelA TAD pull-down Not investigated [32
hGCN1L1 Human general control of amino acid synthesis 1-like 1 GST–RelA TAD pull-down Not investigated [32
IQGAP3 IQ motif-containing GTPase-activating protein 3 GST–RelA TAD pull-down Not investigated [32
TRRAP Transformation/transcription domain-associated protein GST–RelA TAD pull-down Not investigated [32
ATR Ataxia telangiectasia mutated- and Rad3-related GST–RelA TAD pull-down Not investigated [32

In general, the specific subdomains of the TAD with which these proteins interact have not been determined definitively. Moreover, for most of these interactions, the effect of post-translational modifications has not been investigated. One notable exception being Ser536 phosphorylation, the modification studied in most depth, where it has been shown to enhance binding to TAFII31 (TATA-box-binding-protein-associated factor 31), a component of TFIID (transcription factor IID) [23]. Thr505 phosphorylation has also been shown to increase the association of RelA with HDAC1 (histone deacetylase 1), although here it is not known whether the interaction is direct or mediated though a co-repressor protein [21,22]. For many of these interacting proteins, it is also not clear how RelA's dimeric partner might influence their association nor whether their primary role is to affect transactivation or another aspect of RelA behaviour, such as nuclear shuttling.

Given the vast array of genetic targets and activating stimuli, it would be anticipated that many further TAD-interacting proteins remain to be identified. However, a key question that will need to be answered is how these interactions are affected by cellular context, such as the nature of the NF-κB-inducing stimuli and the cell type. Furthermore, it can be expected that the normal balance and control of these diverse interactions will be disrupted in disease states, and this will determine, at least in part, the pathogenic functions of RelA. Therefore understanding these interactions might inform the use and development of new therapies: although NF-κB may not be a direct target of a drug, its function might be regulated indirectly by changes to its post-translational modification state or the activity of a key transcriptional co-regulator.

Transcription: A Biochemical Society Focused Meeting held at the University of Manchester, U.K., 26–28 March 2008 as part of the Gene Expression and Analysis Linked Focused Meetings. Organized and Edited by Stefan Roberts (Manchester, U.K.) and Robert White (Beatson Institute, Glasgow, U.K.).

Abbreviations

     
  • CR

    conserved region

  •  
  • IκB

    inhibitor of nuclear factor κB

  •  
  • IKK

    IκB kinase

  •  
  • NF-κB

    nuclear factor κB

  •  
  • PP

    protein phosphatase

  •  
  • RHD

    Rel homology domain

  •  
  • TAD

    transactivation domain

We thank all members of the Perkins laboratory for their help and assistance. J.O's. is funded by a Wellcome Trust Ph.D. studentship.

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Supplementary data