While the proximal cytoplasmic signalling events controlling the activation of NF-κB are understood in considerable detail, the subsequent intranuclear events that regulate the strength and duration of NF-κB action remain poorly defined. Recently, we have demonstrated that the RelA subunit of the NF-κB 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-κB, including transcriptional activation, DNA binding affinity, I-κBα assembly and subcellular localization. Specifically, acetylation of lysine 221 enhances DNA binding and impairs assembly with I-κBα while acetylation of lysine 310 is required for full transcriptional activity of RelA independent of changes in DNA binding or I-κBα 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-κBα proteins whose expression is activated by NF-κB. I-κBα binding to deacetylated RelA promotes rapid nuclear export of the NF-κB complex. This export is dependent on CRM1 binding to a nuclear export signal present in I-κBα and promotes replenishment of the cytoplasmic pool of latent NF-κB/I-κBα complexes thus readying the cell for response to the next NF-κB 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-κB action.
|Original language||English (US)|
|Number of pages||15|
|Journal||Novartis Foundation Symposium|
|State||Published - 2004|
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