USP2a negatively regulates IL-1-and virus-induced NF-B activation by deubiquitinating TRAF6

The transcription factor NF-B plays critical roles in many biological processes, especially immunity. The signaling to NF-B 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-1- and Sendai virus (SeV)-induced NF-B activation. Overexpression of USP2a inhibited IL-1- and SeV-induced NF-B 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-1 and SeV. Furthermore, USP2a was constitutively associated with TRAF6, and removed K63-linked polyubiquitin chains of TRAF6 induced by IL-1 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-B activation, these findings provide a general regulatory mechanism for NF-B activation triggered by different stimuli.