Editors' ChoiceInnate Immunity

HSV-1 deamidates cGAS

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Sci. Signal.  11 Sep 2018:
Vol. 11, Issue 547, eaav3302
DOI: 10.1126/scisignal.aav3302

An HSV-1 enzyme represses innate immune responses by deamidating the cytosolic DNA sensor cGAS.

Cytosolic DNA from invading pathogens can elicit innate immune responses by stimulating the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase cGAS. The cGAMP produced by this DNA-sensing enzyme activates the adaptor protein STING, which ultimately leads to the expression of genes encoding inflammatory cytokines and interferons. Posttranslational modifications such as phosphorylation, ubiquitylation, and SUMOylation control the activity of cGAS and are targeted by some pathogens to suppress innate responses. Zhang et al. found that the catalytic activity of the deamidase UL37 from herpes simplex virus 1 (HSV-1) was required for the virus to cause lethality in mice and to suppress the production of cGAMP and inflammatory cytokines in primary mouse macrophages and a human monocytic cell line in a manner that depended on cGAS. Expression of UL37 was sufficient to inhibit cGAMP production and cGAS-dependent responses in human cells because it deamidated two asparagine and two glutamine residues in cGAS, thus converting them to aspartate and glutamate, respectively. Deamidation inhibited the cGAMP synthase activity of cGAS but not the ability of cGAS to homodimerize or bind to DNA or nucleotides. Mutant forms of cGAS, in which all four UL37-targeted residues were replaced with the corresponding deamidated residue or only Asn210 was replaced with aspartate, reduced cGAS-dependent responses. Although conserved between mouse, human, and gorilla, Asn210 was not conserved in several other primates. Experiments with wild-type and various mutant forms of primate cGAS homologs revealed that this residue was critical for UL37-mediated deamidation of other residues in cGAS and repression of cGAS-mediated responses. In addition to identifying a virus-induced posttranslational modification that inhibits cGAS, these findings may explain why HSV-1 can infect mice, humans, and gorillas but not other nonhuman primates.

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