2. Academic Validation
  3. Inhibition of lysosome-tethered Ragulator-Rag-3D complex restricts the replication of Enterovirus 71 and Coxsackie A16

Inhibition of lysosome-tethered Ragulator-Rag-3D complex restricts the replication of Enterovirus 71 and Coxsackie A16

  • J Cell Biol. 2023 Dec 4;222(12):e202303108. doi: 10.1083/jcb.202303108.
Xinhui Wang # 1,  Zhilin Hu # 2,  Wei Zhang # 1,  Shuwei Wu 3,  Yongjin Hao 3,  Xia Xiao 4 5,  Jingjing Li 1,  Xiaoliang Yu 1,  Chengkui Yang 1,  Jingfeng Wang 1,  Huiying Zhang 1,  Feng Ma 6,  Weifeng Shi 7,  Jianwei Wang 4 5,  Xiaobo Lei 4 5,  Xiaohu Zhang 3,  Sudan He 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Common Mechanism Research for Major Diseases, and Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China.
  • 2 Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
  • 3 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 4 National Health Commission Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 5 Key Laboratory of Respiratory Disease Pathogenomics, Chinese Academy of Medical Sciences, Beijing, China.
  • 6 National Key Laboratory of Immunity and Inflammation, and Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China.
  • 7 Department of Laboratory Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China.
  • # Contributed equally.
PMID: 37906052 DOI: 10.1083/jcb.202303108
Abstract

Enterovirus 71 (EV71) and Coxsackie A16 (CVA16) are two major causative agents of hand, foot, and mouth disease (HFMD) in young children. However, the mechanisms regulating the replication and pathogenesis of EV71/CVA16 remain incompletely understood. We performed a genome-wide CRISPR-Cas9 knockout screen and identified Ragulator as a mediator of EV71-induced Apoptosis and Pyroptosis. The Ragulator-Rag complex is required for EV71 and CVA16 replication. Upon Infection, the Ragulator-Rag complex recruits viral 3D protein to the lysosomal surface through the interaction between 3D and RagB. Disruption of the lysosome-tethered Ragulator-Rag-3D complex significantly impairs the replication of EV71/CVA16. We discovered a novel EV71 inhibitor, ZHSI-1, which interacts with 3D and significantly reduces the lysosomal tethering of 3D. ZHSI-1 treatment significantly represses replication of EV71/CVA16 as well as virus-induced Pyroptosis associated with viral pathogenesis. Importantly, ZHSI-1 treatment effectively protects against EV71 Infection in neonatal and young mice. Thus, our study indicates that targeting lysosome-tethered Ragulator-Rag-3D may be an effective therapeutic strategy for HFMD.

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