title: USP2a negatively regulates IL-1β- and virus-induced NF-κB activation by deubiquitinating TRAF6.
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.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072,  China.
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Liu
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
mesh_terms: D002460:Cell Line; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D015870:Gene Expression; D055786:Gene Knockout Techniques; D023061:Gene Order; D018390:Gene Targeting; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D029082:Sendai virus / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination; D014780:Viruses / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase