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J Mol Cell Biol. 2013 Feb;5(1):39-47. doi: 10.1093/jmcb/mjs024. Epub 2012 May 19.

USP2a negatively regulates IL-1β- and virus-induced NF-κB activation by deubiquitinating TRAF6.

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  • 1College of Life Sciences, Wuhan University, Wuhan 430072, China.

Abstract

The transcription factor NF-κB plays critical roles in many biological processes, especially immunity. The signaling to NF-κB activation is subtly regulated to avoid harmful immune effects. In this report, we identified ubiquitin-specific protease 2 isoform a (USP2a) as a novel negative regulator in Toll-like receptors/IL-1β- and Sendai virus (SeV)-induced NF-κB activation. Overexpression of USP2a inhibited IL-1β- and SeV-induced NF-κB activation and transcription of inflammatory cytokines, whereas the knockdown or knockout of USP2a had opposite effects. USP2a-deficient cells exhibited potentiated ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) upon stimulation by IL-1β and SeV. Furthermore, USP2a was constitutively associated with TRAF6, and removed K63-linked polyubiquitin chains of TRAF6 induced by IL-1β and SeV stimulation. The residues of USP2a important for their role were also identified. Because of the importance of TRAF6 in multiple pathways leading to NF-κB activation, these findings provide a general regulatory mechanism for NF-κB activation triggered by different stimuli.

PMID:
22611252
DOI:
10.1093/jmcb/mjs024
[PubMed - indexed for MEDLINE]
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