Monkeypox virus protein OPG188 antagonizes cGAS-STING antiviral signaling pathway to mediate immune evasion

• 成果类型: Article
• 署名作者: Pan, Zhaoyi; Zhang, Shujuan; Geng, Xianbo; Wang, Na; Zhang, Lijiang; Wang, Luyao; Yin, Chunhong; Zhang, Huijiao; Liu, Shujun; Zhang, Ling; Fan, Jing; Xue, Guangjian; Li, Rui; Li, Tianle; Yu, Yating; Yao, Hangping; Jin, Changzhong; Wu, Nanping
• 署名单位: Jinan Microecological Biomedicine Shandong Laboratory; Hangzhou Medical College; Shandong Center for Disease Prevention & Control; Shandong First Medical University & Shandong Academy of Medical Sciences; Zhejiang University; Collaborative Innovation Center for Diagnosis & Treatment of Infectious Diseases
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2523334123
• 发表日期: 2026-03-18
• 页码: e2523334123
• 关键词: monkeypoxvirus; cGAS-STING; OPG188; Theaflavin-3'- gallate; NAD plus; dna; apoptosis; DEFENSE

摘要

Innate immune evasion is critical for productive viral replication. Activation of the cGAS-STING antiviral signaling pathway and its downstream effector genes plays a pivotal role in restricting viral replication during early DNA virus infection. Through a comprehensive genomic screen of monkeypox virus (MPXV), we identified three viral genes, OPG147, OPG188, and OPG200, whose expression potently suppresses cGAS-STING pathway activation. Notably, the N-terminal domain of the Poxin protein encoded by OPG188 exhibits nuclease activity and cleaves the cyclic dinucleotide second messenger 2 ' 3 '- cGAMP. Using site-directed mutagenesis, we further delineated nine conserved regions and four key amino acid residues-H15, K140, R182, and I79- within Poxin that are essential for antagonism of cGAS-STING signaling. Moreover, via molecular docking and high-throughput screening of 7,155 small molecules targeting the catalytic pocket of Poxin, we identified two compounds that competitively bind to Poxin, inhibiting its cGAMP-degrading activity and consequently restoring cGAS-STING-mediated antiviral signaling upon MPXV infection. Collectively, these findings underscore the pivotal role of OPG188 in modulating antiviral immune responses and highlight NAD+ and Theaflavin-3'- gallate as promising candidates for the development of anti-MPXV therapeutics.