Regulation at multiple levels of NF-kappaB-mediated transactivation by protein acetylation.

Evidence has accumulated that deacetylation and acetylation events are implicated in the regulation of NF-kappaB transcriptional activity. Several groups have reported potentiation of NF-kappaB-mediated gene induction [by specific inducers (such as TNFalpha)], following deacetylase inhibition by trichostatin A or sodium butyrate. This potentiation reflects a complex acetylation-dependent regulation of NF-kappaB-dependent transactivation. This acetylation-dependent regulation occurs at multiple levels. First, acetylation of histones regulates the NF-kappaB-dependent gene accessibility. Second, unidentified acetylation events modulate temporally the IKK activity and subsequently the duration of NF-kappaB presence and DNA-binding in the nucleus. Third, direct acetylation of the NF-kappaB subunits p65 and p50 regulates different NF-kappaB functions, including transcriptional activation, DNA-binding affinity and IkappaBalpha assembly. Finally, acetyltransferases and deacetylases interact directly with several proteins involved in the NF-kappaB signaling pathway, including NF-kappaB itself, IkappaBalpha, IKKalpha and IKKgamma. These interactions probably allow acetylation of NF-kappaB itself, of other transcription factors and of histones associated with NF-kappaB-regulated genes. The present review discusses these recent data obtained on the role of protein acetylation in the regulation of the NF-kappaB cascade.