ZDHHC11 Promotes DNA Virus-Triggered,MITA-Dependent Innate Immune Signaling

The innate immune response is essential for efficient host defense against viral infections.Upon viral infections,structurally conserved viral components called pathogen-associated molecular patterns(PAMPs)are sensed by pattern recognition receptors(PRRs)in host cells,which triggers signaling pathways that lead to the production of type I interferons,proinflammatory cytokines and other downstream antiviral proteins.These effector proteins act to inhibit viral replication,eradicate virus-infected cells,and facilitate the initiation of adaptive immune response.Viral nucleic acids act as classic PAMPs to initiate innate immune responses.A nucleotidyl transferase family member,cyclic GMP-AMP(cGAMP)synthase(cGAS),was identified as a cytoplasmic DNA sensor in various cell types and in mice.After sensing viral DNA,cGAS catalyzes synthesis of the second messenger molecule cGAMP,which binds to the adaptor MITA(also known as STING,ERIS or MPYS)in the endoplasmic reticulum(ER).MITA plays central roles in the innate immune response to DNA viruses.MITA induces the activation of TBK1 kinase and IRF3 transcription factor,upon sensing of microbial DNAs.How IRF3 is recruited onto the MITA signalosome and how this was modified remain unknown.Here we identified ZDHHC11 a member of DHHC palmitoyl transferase family,as a positive regulator of DNA virus-triggered signaling.First,ZDHHC11 overexpression activates promoters of ISRE,IFNb and NF-kB in reporter assays.Cells down-regulated with ZDHHC11 failed to effectively produce IFNs and other cytokines in response to infection with DNA viruses.Second,Zdhhcll can be greatly induced by infection with DNA but not RNA viruses and in Zdhhc 11-l-mice MEFs,BMDMs and BMDCs showed ZDHHC11 is essential for production of IFN-? and proinflammatory cytokines upon DNA virus infections but not RNA viruses.Zdhhcl l1-/-mice infected with the DNA virms HSV-1 exhibited lower cytokine levels and subsequent higher lethality.Subsequent experiments showed ZDHHC11 is physically associated with MITA and promotes MITA's interactions with IRF3,but has no role in MITA's dimerization or subsequent TBK1 recruitment.Interestingly,the palmitoyl transferase activity is not required for ZDHHCll's role in promoting MITA-mediated signaling.But ZDHHCll enhances the interactions between MITA and ZDHHC3,which has the ability to palmitoylate MITA and then promote TBKl's phosphoralating IRF3.These data suggest ZDHHC11 enhances MITA-mediated innate immune response against DNA viruses by physically bridging MITA with IRF3 and functions as an adapter protein to facilitate the assembly of the MITA signalosome.