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Alpha-herpesvirus US1 interacts with cGAS to suppress type I IFN responses and antiviral defense
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Alpha-herpesvirus US1 interacts with cGAS to suppress type I IFN responses and antiviral defense
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Journal Article
Alpha-herpesvirus US1 interacts with cGAS to suppress type I IFN responses and antiviral defense
2025
Overview
Alpha-herpesviruses, including pseudorabies virus (PRV) and herpes simplex virus type 1 (HSV-1), cause severe diseases in a wide range of hosts. However, the precise mechanisms of immune evasion by alpha-herpesviruses remains elusive, hindering the development of broad-spectrum antiviral vaccines and drugs. Here, we demonstrate that the immediate early protein US1, encoded by alpha-herpesviruses, directly interacts with cGAS, suppressing its dsDNA binding and enzymatic activity. Structural analysis using AlphaFold reveals a conserved overlapping region within PRV and HSV-1 US1 proteins. Deletion of these peptides leads to increased cGAS-mediated IFN-β production. Meanwhile, both synthetic and purified SUMO-fused US1 peptides significantly inhibit cGAS activity across species, with the SUMO-fused US1 peptides directly binding to the catalytic domain of cGAS. Both US1-deficient viruses (PRV-ΔUS1 and HSV-1-ΔUS1) exhibit higher IFN-β production and enhanced signaling through the cGAS-STING pathway. Importantly, mice infected with PRV-ΔUS1 or HSV-1-ΔUS1 show increased IFN-β secretion and reduced viral loads. In conclusion, overlapping peptides from US1 protein of alpha-herpesviruses antagonize cGAS-mediated innate immune responses, highlighting a promising target for the development of broad-spectrum inhibitors to counteract herpesvirus infections.
Publisher
Public Library of Science (PLoS)
Subject
/ Herpesvirus 1, Human - immunology
/ Herpesvirus 1, Human - metabolism
/ Herpesvirus 1, Suid - immunology
/ Humans
/ Interferon Type I - immunology
/ Interferon-beta - immunology
/ Mice
/ Nucleotidyltransferases - genetics
/ Nucleotidyltransferases - immunology
