Duration of Nuclear NF-κB Action Regulated by Reversible Acetylation

Abstract

The nuclear expression and action of the nuclear factor kappa B (NF-kappaB) transcription factor requires signal-coupled phosphorylation and degradation of the IkappaB inhibitors, which normally bind and sequester this pleiotropically active factor in the cytoplasm. The subsequent molecular events that regulate the termination of nuclear NF-kappaB action remain poorly defined, although the activation of de novo IkappaBalpha gene expression by NF-kappaB likely plays a key role. Our studies now demonstrate that the RelA subunit of NF-kappaB is subject to inducible acetylation and that acetylated forms of RelA interact weakly, if at all, with IkappaBalpha. Acetylated RelA is subsequently deacetylated through a specific interaction with histone deacetylase 3 (HDAC3). This deacetylation reaction promotes effective binding to IkappaBalpha and leads in turn to IkappaBalpha-dependent nuclear export of the complex through a chromosomal region maintenance-1 (CRM-1)-dependent pathway. Deacetylation of RelA by HDAC3 thus acts as an intranuclear molecular switch that both controls the duration of the NF-kappaB transcriptional response and contributes to the replenishment of the depleted cytoplasmic pool of latent NF-kappaB-IkappaBalpha complexes.

Aryl hydrocarbon receptor in association with RelA modulates IL-6 expression in non-smoking lung cancer

“…p300/CBP is also able to increase acetylation of RelA, which prolongs NFkB-DNA binding (Chen et al, 2001). On the other hand, histone deacetylase has been reported to reduce RelA acetylation and suppressed NFkB-regulated gene expression (Chen et al, 2001). We also observed that AhR overexpression reduced histone deacetylase activity (data not shown).…”

“…p300/CBP is a coactivator for AhR and NFkB and has histone acetyltransferase activity (Tian, 2009). p300/CBP is also able to increase acetylation of RelA, which prolongs NFkB-DNA binding (Chen et al, 2001). On the other hand, histone deacetylase has been reported to reduce RelA acetylation and suppressed NFkB-regulated gene expression (Chen et al, 2001).…”

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

“…The increase in nuclear NF-kB caused by TSA was partly suppressed in the presence of the NF-kB inhibitor SN50, so TSA may affect the translocation of NF-kB. However, Chen et al 20 reported that TSA prolonged both TNF-induced DNAbinding activity and the presence of NF-kB in the nucleus, delaying the export to the cytoplasm after binding with IkB. Thus, it is more likely that TSA acetylates nuclear p65 and prolongs the retention of NF-kB in the nucleus.…”

“…NF-kB is subjected to reversible acetylation, and HDACs play important roles in its deacetylation. 19,20 Trichostatin A (TSA) is a natural HDACi that promotes histone hyperacetylation and strongly induces apoptosis by altering the expression of some apoptotic genes. [21][22][23] However, it was also reported to show relatively modest antitumor activity in cases of head and neck squamous cell carcinoma (SCC) cells.…”

Copine-I represses NF-κB transcription by endoproteolysis of p65

“…Our laboratory has shown that the activation and repression of NF-kB-responsive genes is a dynamic process, with continual exchanges between co-activator and co-repressor complexes (Hoberg et al, , 2006. Upon the termination of transcriptional activation, much of NF-kB is removed from the nucleus and sequestered in the cytoplasm by newly synthesized IkBa, which resets the pathway for subsequent reactivation (Chen et al, 2001). This mechanism may account for the nuclear export of the NF-kB heterodimer, but it may not account for the termination of NF-kB transcription.…”