NF-κB repression by PIAS3 mediated RelA SUMOylation.
Negative regulation of the NF-κB transcription factor is essential for tissue homeostasis in response to stress and inflammation. NF-κB 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-κB is regulated by SUMOylation, where the RelA subunit of NF-κB is SUMOylated by PIAS3, a member of the PIAS (protein inhibitor of activated STAT) protein family with E3 SUMO ligase activity. PIAS3-mediated NF-κB 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-κB activation thus forming a negative regulatory loop. The SUMOylation of endogenous RelA was enhanced in IκBα null as compared with wild type fibroblasts. The RelA SUMOylation was induced by TNFα 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-κB regulation by PIAS3-mediated RelA SUMOylation.
Department of Dermatology, Oregon Health and Science University, Portland, Oregon, United States of America. liuy@ohsu.edu
Yuangang
Y
Liu
Rebecca
R
Bridges
Aaron
A
Wortham
Molly
M
Kulesz-Martin
D021581:Active Transport, Cell Nucleus; D003001:Cloning, Molecular; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D005347:Fibroblasts; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D016086:Lentivirus; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010957:Plasmids / Q000235:genetics; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism* / Q000494:pharmacology; D058207:Sumoylation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D005231:Fatty Acids, Unsaturated; D016328:NF-kappa B; D050828:Protein Inhibitors of Activated STAT; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases; C038753:leptomycin B