ZDHHC1Modulates Cellular Antiviral Innate Immune Response Against DNA Virus

Innate immune response is critical for efficient host defense against viral infection. Upon viral infection, structurally conserved viral components called pathogen associated-molecular patterns (PAMPs) are recognized by pathogen recognition receptors (PRRs) in the cell, which initiates a series of signaling events that lead to the production of type I interferons, proinflammatory cytokines and other downstream antiviral effecter proteins. These downstream cytokines and effecters act to inhibit viral replication, eradicate virus-infected cells, and facilitate the initiation of adaptive immune response。Recently, a nucleotidyltransferase family member, called cyclic GMP-AMP (cGAMP) synthase (cGAS), has been identified to detect cytosolic DNA in various cell types. Recognition of viral DNA by cGAS leads to the synthesis of the second messenger cGAMP from ATP and GTP. Synthesized cGAMP binds to MITA (also called STING, MPYS, and ERIS), a critical adapter in virus-triggered IFN induction pathways and innate antiviral response. MITA anchors itself in the ER, mitochondria and mitochondrial-associated membrane via its N-terminal transmembrane domains, while its CTD hangs in the cytosol to bind the second messenger cGAMP. Viral infection induces combintion and subsequent signaling to downstream, which serves as a scaffold to assemble IRF3in close proximity to TBK1, leading to TBK1-dependent phosphorylation of IRF3and induction of downstream genes.In this study, we identified ZDHHC1(probable palmitoyltransferase ZDHHC1), an ER-associated protein, as a mediator for type I IFN induction in expression screens. Overexpression of ZDHHC1activated the IFN-β promoter in a dose-dependent manner. While knockdown of ZDHHC1inhibited activation of the IFN-β promoter triggered by transfected poly(I:C) and B-DNA in293cells.Similarly, knockdown of ZDHHC1also inhibited HSV-1-and SeV-triggered expression of the IFNB1in HeLa cells. Gene knockout studies suggest that ZDHHC1-deficiency impaired production of type I IFNs and other cytokines in response to infection with DNA or cGAMP but not RNA viruses. Consistently, Zdhhc1-/-mice were more susceptible to lethal infection by HSV-1but not RNA virus. ZDHHC1constitutively interacted with MITA and was important for homodimerization of MITA and recruitment of downstream components TBK1and IRF3to MITA.Our findings suggest that ZDHHCl plays an important role in innate immune response against DNA but not RNA viruses by modulating MITA activity, and provide important insights into the delicate regulatory mechanisms of innate immune response against DNA viruses.