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Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6

Significance Viral infection activates IRF3 and NF-κB and induces the production of type I interferons and proinflammatory cytokines. In this study, we found that ubiquitin-specific protease 25 (USP25) was required for viral infection-triggered activation of IRF3 and NF-κB and subsequent production of type I IFNs and proinflammatory cytokines. Importantly, the degradation of TRAF3 and TRAF6 was accelerated in Usp25−/− cells compared with wild-type counterparts after viral infection, which could be inhibited by the proteasome inhibitor MG132 and the autophagy inhibitor 3MA, respectively. Reconstitution of TRAF3 and TRAF6 into Usp25−/− MEFs restored virus-triggered production of type I IFNs and proinflammatory cytokines. This study provides insights into an elegant “check and balance” process during innate antiviral responses. Host pathogen-recognition receptors detect nucleic acid from invading viruses and initiate a series of signaling pathways that lead to the production of type I interferons (IFNs) and proinflammatory cytokines. Here, we found that a viral infection-induced deubiquitinase (DUB), ubiquitin-specific protease 25 (USP25) was required for host defense against RNA and DNA viruses. The activation of transcription factors IRF3 and NF-κB was impaired and the production of type I IFNs and proinflammatory cytokines was inhibited in Usp25−/− cells compared with the wild-type counterparts after RNA or DNA viruses infection. Consistently, USP25 deficient mice were more susceptible to H5N1 or HSV-1 infection compared with the wild-type mice. USP25 was associated with TRAF3 and TRAF6 after infection by RNA or DNA viruses and protected virus-induced proteasome-dependent or independent degradation of TRAF3 and TRAF6, respectively. Moreover, reconstitution of TRAF3 and TRAF6 into Usp25−/− MEFs restored virus-triggered production of type I IFNs and proinflammatory cytokines. Our findings thus reveal a previously uncovered positive feedback regulation of innate immune responses against RNA and DNA viruses by USP25.