NF-kappaB repression by PIAS3 mediated RelA SUMOylation.
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Liu Y, Bridges R, Wortham A, Kulesz-Martin M
NF-kappaB repression by PIAS3 mediated RelA SUMOylation.
PLoS One. 2012;7(5):e37636. doi: 10.1371/journal.pone.0037636. Epub 2012 May 23.
- PubMed ID
- 22649547 [ View in PubMed]
- Abstract
Negative regulation of the NF-kappaB transcription factor is essential for tissue homeostasis in response to stress and inflammation. NF-kappaB 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-kappaB is regulated by SUMOylation, where the RelA subunit of NF-kappaB is SUMOylated by PIAS3, a member of the PIAS (protein inhibitor of activated STAT) protein family with E3 SUMO ligase activity. PIAS3-mediated NF-kappaB 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-kappaB activation thus forming a negative regulatory loop. The SUMOylation of endogenous RelA was enhanced in IkappaBalpha null as compared with wild type fibroblasts. The RelA SUMOylation was induced by TNFalpha 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-kappaB regulation by PIAS3-mediated RelA SUMOylation.