Coronaviruses exploit a host cysteine-aspartic protease for replication – Nature.com

Coronaviruses exploit a host cysteine-aspartic protease for replication – Nature.com

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Nature (2022)
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Highly pathogenic coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1,2, Middle East respiratory syndrome coronavirus (MERS-CoV)3, and SARS-CoV-14 vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture5-7 and in patient tissues8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that a cysteine-aspartic protease of the apoptosis cascade, caspase-6, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid (N) proteins, generating N fragments that serve as interferon (IFN) antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss of SARS-CoV-2-infected golden Syrian hamsters and improves the survival of mouse-adapted MERS-CoV (MERS-CoVMA)-infected human DPP4 knock-in (hDPP4 KI) mice. Overall, our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.
These authors contributed equally: Hin Chu, Yuxin Hou
State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
Hin Chu, Anna Jinxia Zhang, Shuofeng Yuan, Jie Zhou, Kin-Hang Kok, Jasper Fuk-Woo Chan & Kwok-Yung Yuen
Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
Hin Chu, Yuxin Hou, Dong Yang, Lei Wen, Huiping Shuai, Chaemin Yoon, Jialu Shi, Yue Chai, Terrence Tsz-Tai Yuen, Bingjie Hu, Cun Li, Xiaoyu Zhao, Yixin Wang, Xiner Huang, Luo Cuiting, Jian-Piao Cai, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Anna Jinxia Zhang, Shuofeng Yuan, Jie Zhou, Kin-Hang Kok, Jasper Fuk-Woo Chan & Kwok-Yung Yuen
Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China
Hin Chu, Anna Jinxia Zhang, Shuofeng Yuan, Jasper Fuk-Woo Chan & Kwok-Yung Yuen
Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China
Hin Chu, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Anna Jinxia Zhang, Shuofeng Yuan, Jie Zhou, Kin-Hang Kok, Dong-Yan Jin, Jasper Fuk-Woo Chan & Kwok-Yung Yuen
Transgenic Core Facility, Centre for Comparative Medicine Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
Kin Shing Lee
Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
Ko-Yung Sit, Dominic Chi-Chung Foo, Wing-Kuk Au & Kenneth Kak-Yuen Wong
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
Dong-Yan Jin
Guangzhou Laboratory, Guangzhou, Guangdong Province, China
Dong-Yan Jin, Jasper Fuk-Woo Chan & Kwok-Yung Yuen
Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
Jasper Fuk-Woo Chan & Kwok-Yung Yuen
Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China
Jasper Fuk-Woo Chan & Kwok-Yung Yuen
Academician Workstation of Hainan Province, Hainan Medical University, Haikou, Hainan, China
Jasper Fuk-Woo Chan & Kwok-Yung Yuen
Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
Jasper Fuk-Woo Chan & Kwok-Yung Yuen
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Correspondence to Hin Chu, Jasper Fuk-Woo Chan or Kwok-Yung Yuen.
This file contains Supplementary Figures 1-5 (Original images for Western blots in main figures and Extended Data figures, and Gating strategy for the flow cytometry experiment in Figure 1), Supplementary Table 1 (Putative caspase-6 cleavage motif in coronavirus N), and Supplementary Table 2 (Primer sequences).
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Chu, H., Hou, Y., Yang, D. et al. Coronaviruses exploit a host cysteine-aspartic protease for replication. Nature (2022). https://doi.org/10.1038/s41586-022-05148-4
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Received: 19 March 2021
Accepted: 26 July 2022
Published: 03 August 2022
DOI: https://doi.org/10.1038/s41586-022-05148-4
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