P300-mediated acetylation of COMMD1 regulates its stability and the ubiquitination/nucleolar translocation of NF-κB/RelA.

Nucleolar sequestration of RelA is an important mechanism for regulating NF-κB transcriptional activity. COMMD1(MURR1) facilitated ubiquitination acts as a critical nucleolar targeting signal for RelA, but how this ubiquitination is regulated, and how it differs from cytokine-mediated ubiquitination which causes proteasomal degradation of RelA, is poorly understood. Here we report a novel role for p300 in controlling stimulus specific ubiquitination of RelA, through modulation of COMMD1. We show that p300 is required for stress-mediated ubiquitination and nucleolar translocation of RelA, but that this effect is indirect. We also demonstrate that COMMD1 is acetylated by p300 and that acetylation protects COMMD1 from XIAP-mediated proteosomal degradation. Furthermore, we demonstrate that COMMD1 acetylation is enhanced by aspirin-mediated stress, and that this acetylation is absolutely required for the protein to bind RelA under these conditions. In contrast, TNF has no effect on COMMD1 acetylation. Finally, we demonstrate these findings have relevance in a whole tissue setting. These data offer a new paradigm for regulating NF-κB transcriptional activity, and the multiple other pathways controlled by COMMD1.
J. Cell. Sci. Jul. 29, 2014; 0(0); [PUBMED:25074812]
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