Sarbecoviruses Suppress Innate Immunity by Recruiting PPM1A to Modulate STAT2 and ORF9b Phosphorylation
Abstract
ABSTRACT Coronaviruses have persistently triggered global pandemics in the 21 st century, featuring either high transmissibility or high pathogenicity. A hallmark of these infections is the delayed activation of innate immune responses, resulting in dysregulated antiviral signaling and uncontrolled viral replication. Multiple viral proteins and hijacked host proteins contribute to immune evasion, representing potential therapeutic targets. Here, we identify viral ORF9b as a conserved accessory protein across the Sarbecovirus subgenus that consistently suppresses innate immune responses by recruiting the protein phosphatase, Mg 2+ /Mn 2+ ‐dependent 1A (PPM1A). Mechanistically, PPM1A exerts dual roles by directly dephosphorylating ORF9b and indirectly downregulating STAT2 phosphorylation, thereby suppressing RIG‐I/MAVS and JAK‐STAT signaling pathways. The PPM1A inhibitor SMIP‐031 inhibits coronavirus replication and restores the antiviral innate immune homeostasis. These findings reveal a conserved immune‐evasion strategy in sarbecoviruses and highlight the ORF9b‐PPM1A axis as a potential target for broad‐spectrum sarbecovirus therapeutics to help prevent future pandemics.
// Source
Authors: Lixiang Xie, Ziye Huang, Zhiyuan Zhang, Yiqiang Zhu, Xiaoqing Liu, Lei Wang, Tongyu Bi, 梁泰鎭, Jintao Lai, Meilin Hu, Qiu Guochang, Shiqi Xiao, Sen Liu, Yaoming Liu, Haiyue Rao, Tao Chen, Haojie Peng, Bin Zhang, Jia Tang, Qianying Li, Yaxin Li, Yuxin Hou, Weibo Yang, Hewei Jiang, Xiancai Ma
Institutions: Shanghai Jiao Tong University, Chinese Academy of Sciences, University of Hong Kong, Sun Yat-sen University, South China University of Technology, University of Chinese Academy of Sciences, Huazhong University of Science and Technology, First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Shanghai Institute of Materia Medica, Guangzhou Laboratory, Guangzhou Institute of Respiratory Health, State Key Laboratory of Drug Research