Abstract
Although the proximal cytoplasmic signaling events that control the activation of the NF-κB transcription factor are understood in considerable detail, the subsequent intranuclear events that regulate the strength and duration of the NF-κB-mediated transcriptional response remain poorly defined. Recent studies have revealed that NF-κB is subject to reversible acetylation and that this posttranslational modification functions as an intranuclear molecular switch to control NF-κB action. In this review, we summarize this new and fascinating mechanism through which the pleiotropic effects of NF-κB are regulated within the cells. NF-κB is a heterodimer composed of p50 and RelA subunits. Both subunits are acetylated at multiple lysine residues with the p300/CBP acetyltransferases playing a major role in this process in vivo. Further, the acetylation of different lysines regulates different functions of NF-κB, including transcriptional activation, DNA binding affinity, IκBα assembly, and subcellular localization. Acetylated forms RelA are subject to deacetylation by histone deacetylase 3 (HDAC3). This selective action of HDAC3 promotes IκBα binding and rapid CRM1-dependent nuclear export of the deacetylated NF-κB complex, which terminates the NF-κB response and replenishes the cytoplasmic pool of latent NF-κB/IκBα complexes. This readies the cell for the next NF-κB-inducing stimulus. Thus, reversible acetylation of RelA serves as an important intranuclear regulatory mechanism that further provides for dynamic control of NF-κB action.
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Abbreviations
- NF-κB :
-
Nuclear factor κB
- RHD :
-
Rel homology domain
- IKK :
-
IκB kinase complex
- TSA :
-
Trichostatin A
- HDAC :
-
Histone deacetylase
- HAT :
-
Histone acetyltransferase
- TNF-α :
-
Tumor necrosis factor α
- NCoR :
-
Nuclear receptor corepressor
- SMRT :
-
Silencing mediator for retinoid and thyroid hormone receptors
- SRC-1, 3 :
-
Steroid receptor coactivator 1, 3
- NIK :
-
NF-κB-inducing kinase
- MEF :
-
Mouse embryo fibroblast
- CRM-1 :
-
Chromosomal region maintenance-1
References
Baldwin AS Jr (1996) The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 14:649–683
Ghosh S, May MJ, Kopp EB (1998) NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260
Baeuerle PA (1998) IκB-NF-κB structures: at the interface of inflammation control. Cell 95:729–731
Karin M (1999) How NF-κB is activated: the role of the IκB kinase (IKK) complex. Oncogene 18:6867–6874
Xiao G, Harhaj EW, Sun SC (2001) NF-κB-inducing kinase regulates the processing of NF-κB2 p100. Mol Cell 7:401–409
Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, et al (2001) Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293:1495–1499
Claudio E, Brown K, Park S, Wang H, Siebenlist U (2002) BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells. Nat Immunol 3:958–965
Coope HJ, Atkinson PG, Huhse B, Belich M, Janzen J, Holman MJ, Klaus GG, Johnston LH, Ley SC (2002) CD40 regulates the processing of NF-κB2 p100 to p52. EMBO J 21:5375–5385
Karin M, Cao Y, Greten FR, Li ZW (2002) NF-κB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2:301–310
Senftleben U, Karin M (2002) The IKK/NF-κB pathway. Crit Care Med 30:S18–S26
Beg AA, Finco TS, Nantermet PV, Baldwin AS Jr (1993) Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of IκBα: a mechanism for NF-κB activation. Mol Cell Biol 13:3301–3310
Brown K, Park S, Kanno T, Franzoso G, Siebenlist U (1993) Mutual regulation of the transcriptional activator NF-κB and its inhibitor, IκBα. Proc Natl Acad Sci U S A 90:2532–2536
Sun SC, Ganchi PA, Ballard DW, Greene WC (1993) NF-κB controls expression of inhibitor IκBα: evidence for an inducible autoregulatory pathway. Science 259:1912–1915
Arenzana-Seisdedos F, Thompson J, Rodriguez MS, Bachelerie F, Thomas D, Hay RT (1995) Inducible nuclear expression of newly synthesized IκBα negatively regulates DNA-binding and transcriptional activities of NF-κB. Mol Cell Biol 15:2689–2696
Arenzana-Seisdedos F, Turpin P, Rodriguez M, Thomas D, Hay RT, Virelizier JL, Dargemont C (1997) Nuclear localization of IκBα promotes active transport of NF-κB from the nucleus to the cytoplasm. J Cell Sci 110:369–378
Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ (1997) Regulation of NF-κB by cyclin-dependent kinases associated with the p300 coactivator. Science 275:523–527
Gerritsen ME, Williams AJ, Neish AS, Moore S, Shi Y, Collins T (1997) CREB-binding protein/p300 are transcriptional coactivators of p65. Proc Natl Acad Sci U S A 94:2927–2932
Sheppard KA, Rose DW, Haque ZK, Kurokawa R, McInerney E, Westin S, Thanos D, Rosenfeld MG, Glass CK, Collins T (1999) Transcriptional activation by NF-κB requires multiple coactivators. Mol Cell Biol 19:6367–6378
Zhong H, Voll RE, Ghosh S (1998) Phosphorylation of NF-κB p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol Cell 1:661–671
Vanden Berghe W, De Bosscher K, Boone E, Plaisance S, Haegeman G (1999) The NF-κB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J Biol Chem 274:32091–32098
Na SY, Lee SK, Han SJ, Choi HS, Im SY, Lee JW (1998) Steroid receptor coactivator-1 interacts with the p50 subunit and coactivates NF-κB-mediated transactivations. J Biol Chem 273:10831–10834
Werbajh S, Nojek I, Lanz R, Costas MA (2000) RAC-3 is a NF-κB coactivator. FEBS Lett 485:195–199
Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW (2002) Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) coactivator activity by IκB kinase. Mol Cell Biol 22:3549–3561
Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, Scheidereit C, Leutz A (1999) The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators. Oncogene 18:3316–3323
Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG (2002) Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-κB and β-amyloid precursor protein. Cell 110:55–67
Lee SK, Kim JH, Lee YC, Cheong J, Lee JW (2000) Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, NF-κB, and serum response factor. J Biol Chem 275:12470–12474
Zhong H, May MJ, Jimi E, Ghosh S (2002) The phosphorylation status of nuclear NF-κB determines its association with CBP/p300 or HDAC-1. Mol Cell 9:625–636
Ashburner BP, Westerheide SD, Baldwin AS Jr (2001) The p65 (RelA) subunit of NF-κB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol Cell Biol 21:7065–7077
Chen LF, Fischle W, Verdin E, Greene WC (2001) Duration of nuclear NF-κB action regulated by reversible acetylation. Science 293:1653–1657
Berger SL (1999) Gene activation by histone and factor acetyltransferases. Curr Opin Cell Biol 11:336–341
Imhof A, Yang XJ, Ogryzko VV, Nakatani Y, Wolffe AP, Ge H (1997) Acetylation of general transcription factors by histone acetyltransferases. Curr Biol 7:689–692
Kuo MH, Allis CD (1998) Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 20:615–626
Cheung WL, Briggs SD, Allis CD (2000) Acetylation and chromosomal functions. Curr Opin Cell Biol 12:326–333
Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90:595–606
Sterner DE, Berger SL (2000) Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 64:435–459
Martínez-Balbás MA, Bauer UM, Nielsen SJ, Brehm A, Kouzarides T (2000) Regulation of E2F1 activity by acetylation. EMBO J 19:662–671
Chen H, Tini M, Evans RM (2001) HATs on and beyond chromatin. Curr Opin Cell Biol 13:218–224
Gronroos E, Hellman U, Heldin CH, Ericsson J (2002) Control of Smad7 stability by competition between acetylation and ubiquitination. Mol Cell 10:483–493
Furia B, Deng L, Wu K, Baylor S, Kehn K, Li H, Donnelly R, Coleman T, Kashanchi F (2002) Enhancement of NF-κB acetylation by coactivator p300 and HIV-1 Tat proteins. J Biol Chem 277:4973–4980
Kiernan R, Bres V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, Jin DY, Emiliani S, Benkirane M (2003) Post-activation turn-off of NF-κB-dependent transcription is regulated by acetylation of p65. J Biol Chem 278:2758–2766
Chen LF, Mu Y, Greene WC (2002) Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-κB. EMBO J 21:6539–6548
Hamamori Y, Sartorelli V, Ogryzko V, Puri PL, Wu HY, Wang JY, Nakatani Y, Kedes L (1999) Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A. Cell 96:405–413
Chakravarti D, Ogryzko V, Kao HY, Nash A, Chen H, Nakatani Y, Evans RM (1999) A viral mechanism for inhibition of p300 and PCAF acetyltransferase activity. Cell 96:393–403
Munshi N, Merika M, Yie J, Senger K, Chen G, Thanos D (1998) Acetylation of HMG I(Y) by CBP turns off IFNβ expression by disrupting the enhanceosome. Mol Cell 2:457–467
Wen YD, Perissi V, Staszewski LM, Yang WM, Krones A, Glass CK, Rosenfeld MG, Seto E (2000) The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc Natl Acad Sci U S A 97:7202–7207
Guenther MG, Barak O, Lazar MA (2001) The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol Cell Biol 21:6091–6101
Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E (2002) Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell 9:45–57
Espinosa L, Ingles-Esteve J, Robert-Moreno A, Bigas A (2003) IκBα and p65 regulate the cytoplasmic shuttling of nuclear corepressors: cross-talk between notch and NF-κB pathways. Mol Biol Cell 14:491–502
Espinosa L, Santos S, Ingles-Esteve J, Munoz-Canoves P, Bigas A (2002) p65-NF-κB synergizes with notch to activate transcription by triggering cytoplasmic translocation of the nuclear receptor corepressor N-CoR. J Cell Sci 115:1295–1303
Quivy V, Adam E, Collette Y, Demonte D, Chariot A, Vanhulle C, Berkhout B, Castellano R, de Launoit Y, Burny A, et al (2002) Synergistic activation of human immunodeficiency virus type 1 promoter activity by NF-κB and inhibitors of deacetylases: potential perspectives for the development of therapeutic strategies. J Virol 76:11091–11103
Mujtaba S, He Y, Zeng L, Farooq A, Carlson JE, Ott M, Verdin E, Zhou MM (2002) Structural basis of lysine-acetylated HIV-1 Tat recognition by PCAF bromodomain. Mol Cell 9:575–586
Owen DJ, Ornaghi P, Yang JC, Lowe N, Evans PR, Ballario P, Neuhaus D, Filetici P, Travers AA (2000) The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p. EMBO J 19:6141–6149
Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM (1999) Structure and ligand of a histone acetyltransferase bromodomain. Nature 399:491–496
Polesskaya A, Naguibneva I, Duquet A, Bengal E, Robin P, Harel-Bellan A (2001) Interaction between acetylated MyoD and the bromodomain of CBP and/or p300. Mol Cell Biol 21:5312–5320
Deng WG, Zhu Y, Wu KK (2003) Up-regulation of p300 binding and p50 acetylation in TNF-α-induced cyclooxygenase-2 promoter activation. J Biol Chem 278:4770–4777
Boyes J, Byfield P, Nakatani Y, Ogryzko V (1998) Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 396:594–598
Li S, Aufiero B, Schiltz RL, Walsh MJ (2000) Regulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP. Proc Natl Acad Sci U S A 97:7166–7171
Chen FE, Huang DB, Chen YQ, Ghosh G (1998) Crystal structure of p50/p65 heterodimer of transcription factor NF-κB bound to DNA. Nature 391:410–413
Zhang Q, Yao H, Vo N, Goodman RH (2000) Acetylation of adenovirus E1A regulates binding of the transcriptional corepressor CtBP. Proc Natl Acad Sci U S A 97:14323–14328
Huxford T, Huang DB, Malek S, Ghosh G (1998) The crystal structure of the IκBα/NF-κB complex reveals mechanisms of NF-κB inactivation. Cell 95:759–770
Jacobs MD, Harrison SC (1998) Structure of an IκBα/NF-κB complex. Cell 95:749–758
Soutoglou E, Viollet B, Vaxillaire M, Yaniv M, Pontoglio M, Talianidis I (2001) Transcription factor-dependent regulation of CBP and P/CAF histone acetyltransferase activity. EMBO J 20:1984–1992
Spilianakis C, Papamatheakis J, Kretsovali A (2000) Acetylation by PCAF enhances CIITA nuclear accumulation and transactivation of major histocompatibility complex class II genes. Mol Cell Biol 20:8489–8498
Vermeulen L, De Wilde G, Damme PV, Vanden Berghe W, Haegeman G (2003) Transcriptional activation of the NF-κB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 22:1313–1324
Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S (1997) The transcriptional activity of NF-κB is regulated by the IκB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell 89:413–424
Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W (1999) IκB kinases phosphorylate NF-κB p65 subunit on serine 536 in the transactivation domain. J Biol Chem 274:30353–30356
Wang D, Westerheide SD, Hanson JL, Baldwin AS Jr (2000) TNF-α-induced phosphorylation of RelA/p65 on Ser 529 is controlled by casein kinase II. J Biol Chem 275:32592–32597
Sakaguchi K, Herrera JE, Saito S, Miki T, Bustin M, Vassilev A, Anderson CW, Appella E (1998) DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev 12:2831–2841
Liu L, Scolnick DM, Trievel RC, Zhang HB, Marmorstein R, Halazonetis TD, Berger SL (1999) p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol Cell Biol 19:1202–1209
Chan HM, Krstic-Demonacos M, Smith L, Demonacos C, La Thangue NB (2001) Acetylation control of the retinoblastoma tumour-suppressor protein. Nat Cell Biol 3:667–674
Acknowledgements
This work was supported in part by a National Institutes of Health grant (RO1 CA89001–02) to W.C.G., a National Institutes of Health training grant (T32 AI07305) to L.F.C., and by funds from the J. David Gladstone Institutes, and Pfizer,, and benefited from core facilities provided through the UCSF-GIVI Center for AIDS Research (National Institutes of Health Grant P30 MH59037). The authors thank R. Givens and S. Cammack for manuscript preparation, J. Carroll and C. Goodfellow for graphics, and G. Howard and S. Ordway for editorial assistance.
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Chen, LF., Greene, W.C. Regulation of distinct biological activities of the NF-κB transcription factor complex by acetylation. J Mol Med 81, 549–557 (2003). https://doi.org/10.1007/s00109-003-0469-0
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DOI: https://doi.org/10.1007/s00109-003-0469-0