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Review
. 2004:259:208-17; discussion 218-25.

Regulation of NF-kappaB action by reversible acetylation

Warner C Greene  1 , Lin-feng Chen
Affiliations
  • PMID: 15171256
Review

Regulation of NF-kappaB action by reversible acetylation

Warner C Greene et al. Novartis Found Symp. 2004.

Abstract

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.

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