Regulation of NF-kappaB action by reversible acetylation.
While the proximal cytoplasmic signalling events controlling the activation of NF-kappaB are understood in considerable detail, the subsequent intranuclear events that regulate the strength and duration of NF-kappaB action remain poorly defined. Recently, we have demonstrated that the RelA subunit of the NF-kappaB heterodimer is subject to reversible acetylation. The p300/CBP acetyltransferases play a major role in the in vivo acetylation of RelA principally targeting lysines 218, 221 and 310 for modification. Acetylation of these distinct lysine residues regulates different functions of NF-kappaB, including transcriptional activation, DNA binding affinity, I-kappaBalpha assembly and subcellular localization. Specifically, acetylation of lysine 221 enhances DNA binding and impairs assembly with I-kappaBalpha while acetylation of lysine 310 is required for full transcriptional activity of RelA independent of changes in DNA binding or I-kappaBalpha binding. In turn, acetylated RelA is deacetylated by histone deacetylase 3 (HDAC3). Deacetylation of lysine 221 promotes high-affinity binding of RelA to newly synthesized I-kappaBalpha proteins whose expression is activated by NF-kappaB. I-kappaBalpha binding to deacetylated RelA promotes rapid nuclear export of the NF-kappaB complex. This export is dependent on CRM1 binding to a nuclear export signal present in I-KBalpha and promotes replenishment of the cytoplasmic pool of latent NF-kappaB/I-kappaBalpha complexes thus readying the cell for response to the next NF-kappaB inducing stimulus Together, these studies highlight how reversible acetylation of RelA serves as an intranuclear molecular switch promoting both positive and negative regulatory effects on nuclear NF-kappaB action.
Greene
Warner C
WC
Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA 94141, USA.
Chen
Lin-feng
LF
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D051996:Transcription Factor RelA; D014157:Transcription Factors; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D004247:DNA; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D020672:I-kappa B Proteins; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3