Regulation of distinct biological activities of the NF-kappaB transcription factor complex by acetylation.
Although the proximal cytoplasmic signaling events that control the activation of the NF-kappaB transcription factor are understood in considerable detail, the subsequent intranuclear events that regulate the strength and duration of the NF-kappaB-mediated transcriptional response remain poorly defined. Recent studies have revealed that NF-kappaB is subject to reversible acetylation and that this posttranslational modification functions as an intranuclear molecular switch to control NF-kappaB action. In this review, we summarize this new and fascinating mechanism through which the pleiotropic effects of NF-kappaB are regulated within the cells. NF-kappaB 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-kappaB, including transcriptional activation, DNA binding affinity, IkappaBalpha assembly, and subcellular localization. Acetylated forms RelA are subject to deacetylation by histone deacetylase 3 (HDAC3). This selective action of HDAC3 promotes IkappaBalpha binding and rapid CRM1-dependent nuclear export of the deacetylated NF-kappaB complex, which terminates the NF-kappaB response and replenishes the cytoplasmic pool of latent NF-kappaB/IkappaBalpha complexes. This readies the cell for the next NF-kappaB-inducing stimulus. Thus, reversible acetylation of RelA serves as an important intranuclear regulatory mechanism that further provides for dynamic control of NF-kappaB action.
Chen
Lin-Feng
LF
Gladstone Institute of Virology and Immunology, University of California, P.O. Box 419100, San Francisco, CA 94141-9100, USA.
Greene
Warner C
WC
D000107:Acetylation; D000123:Acetyltransferases / Q000494:pharmacology; D000818:Animals; D018797:Cell Cycle Proteins / Q000494:pharmacology; D051548:Histone Acetyltransferases; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051996:Transcription Factor RelA; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor