Mechanisms Of Deubiquitin Enzyme OTUD4-Mediated Positive Regulation Of Antiviral Responses

Invading pathogens induce detection of pathogen-associated molecular patterns(PAMPs)by host pattern-recognition receptors(PRRs),then trigger downstream signal transduction and the induction of type I interferons and proinflammatory cytokines,and initiate the innate immune responses.The retinoic acid-inducible gene I like receptors(RLRs,including RIG-I and MDA5)of host cells recognize cytoplasmic double-stranded RNA or single-stranded RNA produced during RNA virus infection and replication,and recruit the key adaptor protein mitochondrial antiviral signaling protein MAVS(also known as VISA,CARDIF and IPS-1).Then RLRs induce MAVS oligomerization to recruit TNF receptor-associated factors(TRAFs),TBK1 and a series of downstream signal transduction protein,thereby promote the activation of transcription factors IRF3 and NF-?B and induce the antiviral gene transcription and expression.This study finds that OTUD4(ovarian tumor family deubiquitinase 4)positively regulates anti-RNA virus innate immunity by targeting MAVS.RNA virus infection leads to OTUD4 expression upregulation.OTUD4 interacts with MAVS to remove K48-linked polyubiquitin chains and protects MAVS from proteasome-dependent degradation,and promotes antiviral innate immunity.In addition,the deubiquitination enzyme activity is indispensable for this process.Consistently,knockdown or knockout of OTUD4 inhibits RNA virus induced activation of IRF3 and NF-?B,reduces expression of downstream genes,and potentiates VSV replication.Furthermore,Cre-ER Otud4~fl/fll/fl and Lyz2-Cre Otud4~fl/fll/fl mice are more sensitive to VSV infection and produce less type I interferons and proinflammatory cytokines compared to their littermates.Moreover,reconstitution of OTUD4 or MAVS into OTUD4 deficient cells repairs cellular antiviral ability.Together,this study reveals OTUD4 is a new positive regulator in virus-triggered signaling.