Alpha-herpesvirus US1 interacts with cGAS to suppress type I IFN responses and antiviral defense
文献类型: 外文期刊
作者: 曲伟艺;;袁烨;;沈冬冬;;张纪文;;黄翔宇;;赵东明;;李鑫
关键词: 疱疹病毒;;蛋白相互作用;;Ⅰ型干扰素;;抗病毒防御
期刊名称: PLoS Pathogens
ISSN: 1553-7366
年卷期: 2025 年
页码:
收录情况: SCIE(2025版)
摘要: 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 overlap- ping 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, high- lighting a promising target for the development of broad-spectrum inhibitors to coun- teract herpesvirus infections.
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