NF-?B repression by PIAS3 mediated RelA SUMOylation.

ABSTRACT: Negative regulation of the NF-?B transcription factor is essential for tissue homeostasis in response to stress and inflammation. NF-?B activity is regulated by a variety of biochemical mechanisms including phosphorylation, acetylation, and ubiquitination. In this study, we provide the first experimental evidence that NF-?B is regulated by SUMOylation, where the RelA subunit of NF-?B is SUMOylated by PIAS3, a member of the PIAS (protein inhibitor of activated STAT) protein family with E3 SUMO ligase activity. PIAS3-mediated NF-?B repression was compromised by either RelA mutant resistant to SUMOylation or PIAS3 mutant defective in SUMOylation. PIAS3-mediated SUMOylation of endogenous RelA was induced by NF-?B activation thus forming a negative regulatory loop. The SUMOylation of endogenous RelA was enhanced in I?B? null as compared with wild type fibroblasts. The RelA SUMOylation was induced by TNF? but not leptomycin B mediated RelA nuclear translocation. Furthermore, RelA mutants defective in DNA binding were not SUMOylated by PIAS3, suggesting that RelA DNA binding is a signal for PIAS3-mediated SUMOylation. These results support a novel negative feedback mechanism for NF-?B regulation by PIAS3-mediated RelA SUMOylation.

SUBMITTER: Liu Y 

PROVIDER: S-EPMC3359287 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature