OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING.

Stimulator of interferon genes (STING) is an adaptor protein that is critical for effective innate antiviral and antitumor immunity. The activity of STING is heavily regulated by protein ubiquitination, which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases. Here, we report that the deubiquitinase OTUD5 interacts with STING, cleaves its K48-linked polyubiquitin chains, and promotes its stability. Consistently, knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation. More importantly, Lyz2-Cre Otud5fl/Y mice and CD11-Cre Otud5fl/Y mice showed more susceptibility to herpes simplex virus type 1 (HSV-1) infection and faster development of melanomas than their corresponding control littermates, indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity. Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.