Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

Abstract

The DNA sensor cyclic GMP-AMP synthase (cGAS) is critical in host antiviral immunity. Vaccinia virus (VACV) is a large cytoplasmic DNA virus that belongs to the poxvirus family. How vaccinia virus antagonizes the cGAS-mediated cytosolic DNA-sensing pathway is not well understood. In this study, we screened 80 vaccinia genes to identify potential viral inhibitors of the cGAS/Stimulator of interferon gene (STING) pathway. We discovered that vaccinia E5 is a virulence factor and a major inhibitor of cGAS. E5 is responsible for abolishing cGAMP production during vaccinia virus (Western Reserve strain) infection of dendritic cells. E5 localizes to the cytoplasm and nucleus of infected cells. Cytosolic E5 triggers ubiquitination of cGAS and proteasome-dependent degradation via interacting with cGAS. Deleting the E5R gene from the Modified vaccinia virus Ankara (MVA) genome strongly induces type I IFN production by dendritic cells (DCs) and promotes DC maturation, and thereby improves antigen-specific T cell responses.

Oncolytic vaccinia virus immunotherapy antagonizes image-guided radiotherapy in mouse mammary tumor models

“…Several apoptotic inhibitors are encoded by these viruses [ 44 ]. Most notably VACV B2R encodes a cGAMP nuclease [ 45 ] and E5R was also recently shown to encode an inhibitor of the DNA sensor cGAS [ 46 ]. The cGAS-STING pathway provides an important link between radiation and the immune response to radiation.…”

The parapoxvirus Orf virus inhibits dsDNA-mediated type I IFN expression via STING-dependent and STING-independent signalling pathways

“…VACV C16 and C4 were shown to antagonize the activation of DNA-PK by interacting with the Ku heterodimer and thereby disrupting the binding of the Ku heterodimer to DNA, resulting in inhibition of DNA-PK-mediated DNA sensing [81–83]. It has been recently discovered that VACV E5 antagonizes cGAS and promotes its degradation and abolishes cGAMP production [84]. In addition, a cGAMP-specific degrading enzyme called poxvirus immune nuclease (poxin) was discovered that cleaves cGAMP resulting in STING inhibition [85, 86].…”

“…Studies have shown that STING is targeted by many DNA viruses as reviewed in [98]. Georgana et al [73] have found that poxviruses like VACV, CPXV and ECTV, but not MVA, were able to interfere with DNA-induced STING signalling by inhibiting STING dimerization and phosphorylation, and this inhibition capacity in orthopoxviruses could be explained, at least in part, by the action of poxins and E5 orthologues as mentioned above [84–86]. HSV-1 also antagonizes the response by encoding VP22 protein that act upstream of the cGAS-STING pathway through interfering with enzymatic activity of cGAS [99].…”

Activating neutrophils by co-administration of immunogenic recombinant modified vaccinia virus Ankara and granulocyte colony-stimulating factor for the treatment of malignant peripheral nerve sheath tumor

“…E3 antagonizes dsRNA-sensing pathway mediated by MDA5/MAVS 34 . WR199 encodes a 68-KDa ankyrin repeat/F-box protein 35 , another cGAS inhibitor 28 .…”

“…To improve MVA-based cancer immunotherapy, we have now engineered first and second generations of recombinant MVA viruses. Our first-generation recombinant MVA (rMVA/MQ710) was engineered to delete a viral immune evasion gene E5R, which encodes a potent inhibitor of cGAS 28 , and to express two transgenes including Flt3L and OX40L 29 . IT rMVA/MQ710 (MVAΔE5R-Flt3L-OX40L) generates potent antitumor immunity, dependent on CD8 + T cells, the cGAS/STING, and type I IFN signaling.…”