Abstract
Cyclic GMP-AMP synthase (cGAS) senses viral DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the ER-localized adaptor protein Mediator of IRF3 Activator (MITA) to initiate innate antiviral response. Human cytomegalovirus (HCMV) proteins can antagonize host immune responses to promote latent infection. Here, we identified HCMV UL42 as a negative regulator of cGAS/MITA-dependent antiviral response. UL42-deficiency enhances HCMV-induced production of type I interferons (IFNs) and downstream antiviral genes. Consistently, wild-type HCMV replicates more efficiently than UL42-deficient HCMV. UL42 interacts with both cGAS and MITA. UL42 inhibits DNA binding, oligomerization and enzymatic activity of cGAS. UL42 also impairs translocation of MITA from the ER to perinuclear punctate structures, which is required for MITA activation, by facilitating p62/LC3B-mediated degradation of translocon-associated protein β (TRAPβ). These results suggest that UL42 can antagonize innate immune response to HCMV by targeting the core components of viral DNA-triggered signaling pathways.
Highlights
The innate immune system is the first line of host defense against microbial infection
We found that human cytomegalovirus (HCMV) protein UL42 inhibits innate antiviral responses promotes HCMV replication
We established human primary foreskin fibroblasts (HFFs) cell lines that stably express UL42 (HFF-UL42) by lentiviral-mediated transduction (Fig 1C). qPCR analysis indicated that induction of antiviral genes including IFNB1, ISG56 and CXCL10 following infection with the DNA viruses HCMV, herpes simplex virus 1 (HSV-1), and vaccinia virus (VACV) was inhibited in HFF-UL42 as compared to empty vector-transduced control cells (HFF-Vec) (Fig 1C)
Summary
The innate immune system is the first line of host defense against microbial infection. Cellular pattern recognition receptors (PRRs) recognize structurally conserved microbial components called pathogen-associated molecular patterns (PAMPs), which triggers a series of signaling events that lead to the induction of type I interferons (IFNs), proinflammatory cytokines and other downstream effectors. These effectors mediate the inhibition of microbial replication, clearance of infected cells and facilitation of adaptive immune response to eliminate infected pathogens [1,2,3,4]. MITA recruits TANK-binding kinase 1(TBK1) and interferon regulatory factor 3 (IRF3), leading to induction of type I interferons and other antiviral effectors [17]
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