Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication.

Abstract

Herpes simplex virus 1 (HSV-1) establishes infections in humans and mice, but some non-human primates exhibit resistance via unknown mechanisms. Innate immune recognition pathways are highly conserved but are pivotal in determining susceptibility to DNA virus infections. We report that variation of a single amino acid residue in the innate immune sensor cGAS determines species-specific inactivation by HSV-1. The HSV-1 UL37 tegument protein deamidates human and mouse cGAS. Deamidation impairs the ability of cGAS to catalyze cGAMP synthesis, which activates innate immunity. HSV-1 with deamidase-deficient UL37 promotes robust antiviral responses and is attenuated in mice in a cGAS- and STING-dependent manner. Mutational analyses identified a single asparagine in human and mouse cGAS that is not conserved in many non-human primates. This residue underpins UL37-mediated cGAS deamidation and species permissiveness of HSV-1. Thus, HSV-1 mediates cGAS deamidation for immune evasion and exploits species sequence variation to disarm host defenses.

• Authors: Junjie Zhang, Jun Zhao, Simin Xu, Junhua Li, Shanping He, Yi Zeng, Linshen Xie, Na Xie, Ting Liu, Katie Lee, Gil Ju Seo, Lin Chen, Alex C Stabell, Zanxian Xia, Sara L Sawyer, Jae Jung, Canhua Huang, Pinghui Feng
• Journal: Cell host & microbe (Cell Host Microbe) Vol. 24 Issue 2 Pg. 234-248.e5 (08 08 2018) ISSN: 1934-6069 [Electronic] United States
• PMID: 30092200 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Nucleotides, Cyclic
• Sting1 protein, mouse
• UL37 protein, Human herpesvirus 1
• Viral Structural Proteins
• cyclic guanosine monophosphate-adenosine monophosphate
• Nucleotidyltransferases
• cGAS protein, human
• cGAS protein, mouse

Topics

• Animals
• Female
• Herpesvirus 1, Human (pathogenicity, physiology)
• Host-Pathogen Interactions (physiology)
• Immunity, Innate
• Male
• Membrane Proteins (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Nucleotides, Cyclic (metabolism)
• Nucleotidyltransferases (genetics, metabolism)
• Primates
• Species Specificity
• Viral Structural Proteins (genetics, metabolism)
• Virus Replication