2. Academic Validation
  3. Coronaviruses exploit a host cysteine-aspartic protease for replication

Coronaviruses exploit a host cysteine-aspartic protease for replication

  • Nature. 2022 Sep;609(7928):785-792. doi: 10.1038/s41586-022-05148-4.
Hin Chu  # 1 2 3 4,  Yuxin Hou  # 5,  Dong Yang 5,  Lei Wen 5,  Huiping Shuai 5,  Chaemin Yoon 5,  Jialu Shi 5,  Yue Chai 5,  Terrence Tsz-Tai Yuen 5,  Bingjie Hu 5,  Cun Li 5,  Xiaoyu Zhao 5,  Yixin Wang 5,  Xiner Huang 5,  Kin Shing Lee 6,  Cuiting Luo 5,  Jian-Piao Cai 5,  Vincent Kwok-Man Poon 5 7,  Chris Chung-Sing Chan 5 7,  Anna Jinxia Zhang 8 5 9 7,  Shuofeng Yuan 8 5 9 7,  Ko-Yung Sit 10,  Dominic Chi-Chung Foo 10,  Wing-Kuk Au 10,  Kenneth Kak-Yuen Wong 10,  Jie Zhou 8 5 7,  Kin-Hang Kok 8 5 7,  Dong-Yan Jin 7 11 12,  Jasper Fuk-Woo Chan 13 14 15 16 17 18 19 20 21,  Kwok-Yung Yuen 22 23 24 25 26 27 28 29 30
Affiliations

Affiliations

  • 1 State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. hinchu@hku.hk.
  • 2 Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. hinchu@hku.hk.
  • 3 Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. hinchu@hku.hk.
  • 4 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Sha Tin, China. hinchu@hku.hk.
  • 5 Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
  • 6 Transgenic Core Facility, Centre for Comparative Medicine Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
  • 7 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Sha Tin, China.
  • 8 State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
  • 9 Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 10 Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
  • 11 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
  • 12 Guangzhou Laboratory, Guangzhou, China.
  • 13 State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. jfwchan@hku.hk.
  • 14 Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. jfwchan@hku.hk.
  • 15 Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. jfwchan@hku.hk.
  • 16 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Sha Tin, China. jfwchan@hku.hk.
  • 17 Guangzhou Laboratory, Guangzhou, China. jfwchan@hku.hk.
  • 18 Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. jfwchan@hku.hk.
  • 19 Department of Microbiology, Queen Mary Hospital, Pokfulam, China. jfwchan@hku.hk.
  • 20 Academician Workstation of Hainan Province, Hainan Medical University, Haikou, China. jfwchan@hku.hk.
  • 21 Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, China. jfwchan@hku.hk.
  • 22 State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. kyyuen@hku.hk.
  • 23 Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. kyyuen@hku.hk.
  • 24 Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. kyyuen@hku.hk.
  • 25 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Sha Tin, China. kyyuen@hku.hk.
  • 26 Guangzhou Laboratory, Guangzhou, China. kyyuen@hku.hk.
  • 27 Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. kyyuen@hku.hk.
  • 28 Department of Microbiology, Queen Mary Hospital, Pokfulam, China. kyyuen@hku.hk.
  • 29 Academician Workstation of Hainan Province, Hainan Medical University, Haikou, China. kyyuen@hku.hk.
  • 30 Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, China. kyyuen@hku.hk.
  • # Contributed equally.
PMID: 35922005 DOI: 10.1038/s41586-022-05148-4
Abstract

Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs. 1,2) (SARS-CoV-2), Middle East respiratory syndrome coronavirus3 (MERS-CoV) and SARS-CoV-1 (ref. 4), 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 caspase-6, a cysteine-aspartic protease of the Apoptosis cascade, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid proteins, generating fragments that serve as interferon antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss in golden Syrian hamsters infected with SARS-CoV-2 and improves the survival of mice expressing human DPP4 that are infected with mouse-adapted MERS-CoV. Our study reveals how coronaviruses exploit a component of the host Apoptosis cascade to facilitate virus replication.

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