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Regulation of distinct biological activities of the NF-κB transcription factor complex by acetylation

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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

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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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Correspondence to Warner C. Greene.

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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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