Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

摘要

The activity and stability of the adapter protein MAVS (also known as VISA,Cardif and IPS-1),which critically mediates cellular antiviral responses,are extensively regulated by ubiquitination.However,the process whereby MAVS is deubiquitinated is unclean Here,we report that the ovarian tumor family deubiquitinase 4 (OTUD4) targets MAVS for deubiquitination.Viral infection leads to the IRF3/7-dependent upregulation of OTUD4 which interacts with MAVS to remove K48-linked polyubiquitin chains,thereby maintaining MAVS stability and promoting innate antiviral signaling.Knockout or knockdown of OTUD4 impairs RNA virus-triggered activation of IRF3 and NF-KB,expression of their downstream target genes,and potentiates VSV replication in vitro and in vivo.Consistently,Cre-ER Otud4fl/fl or Lyz2-Cre Otud4fl/fl mice produce decreased levels of type Ⅰ interferons and proinflammatory cytokines and exhibit increased sensitivity to VSV infection compared to their control littermates.In addition,reconstitution of MAVS into OTUD4-deficient cells restores virus-induced expression of downstream genes and cellular antiviral responses.Together,our findings uncover an essential role of OTUD4 in virus-triggered signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.