Regulation of NF-kappaB action by reversible acetylation

Novartis Found Symp. 2004;259:208-17; discussion 218-25.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Acetylation
  • Acetyltransferases / metabolism*
  • Cell Cycle Proteins / metabolism
  • DNA / metabolism
  • Gene Expression Regulation / physiology*
  • Histone Acetyltransferases
  • Histone Deacetylases / metabolism
  • Humans
  • I-kappa B Proteins / metabolism
  • NF-kappa B / metabolism*
  • Transcription Factor RelA
  • Transcription Factors
  • Transcriptional Activation*
  • p300-CBP Transcription Factors

Substances

  • Cell Cycle Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • Transcription Factor RelA
  • Transcription Factors
  • DNA
  • Acetyltransferases
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Histone Deacetylases
  • histone deacetylase 3