USP8‐Governed MDA5 Homeostasis Promotes Innate Immunity and Autoimmunity

Abstract The essential cytoplasmic RNA sensor Melanoma Differentiation‐Associated protein 5 (MDA5) initiates type I interferons (IFNs) signaling and subsequent immune responses. However, aberrant activation of MDA5 by viral infections or gain‐of‐function mutations leads to severe autoimmune diseases, for most of which effective treatment is limited. Here, it is shown that inactivation of ubiquitin‐specific protease 8 (USP8/UBPy) degrades the MDA5 protein, suppressing antiviral signaling and autoimmunity. It is found that viral infection modulates the AKT‐dependent phosphorylation of USP8 at serine 718, which not only promotes the activation of USP8 but also enhances the association between USP8 and MDA5 and the consequent deubiquitination and stabilization of MDA5. Inactivation of USP8 specifically degrades the MDA5 protein regardless of the mutation pattern. Genetic deletion of Usp8 in mice contributes to decreased levels of type I interferons and proinflammatory cytokines. Importantly, inhibition of USP8 or AKT can effectively suppress MDA5‐induced autoimmunity in Aicardi–Goutières syndrome (AGS) mice and anti‐MDA5‐positive dermatomyositis (DM)/systemic lupus erythematosus (SLE) patient cells. Therefore, these results highlight the critical roles of USP8 in innate antiviral immunity against RNA viruses and autoimmunity and provide a potential therapy for treating autoimmune diseases associated with MDA5.