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.