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
  • 1. State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. [email protected].
  • 2. Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. [email protected].
  • 3. Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. [email protected].
  • 4. Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Sha Tin, China. [email protected].
  • 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. [email protected].
  • 14. Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. [email protected].
  • 15. Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. [email protected].
  • 16. Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Sha Tin, China. [email protected].
  • 17. Guangzhou Laboratory, Guangzhou, China. [email protected].
  • 18. Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. [email protected].
  • 19. Department of Microbiology, Queen Mary Hospital, Pokfulam, China. [email protected].
  • 20. Academician Workstation of Hainan Province, Hainan Medical University, Haikou, China. [email protected].
  • 21. Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, China. [email protected].
  • 22. State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. [email protected].
  • 23. Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. [email protected].
  • 24. Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. [email protected].
  • 25. Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Sha Tin, China. [email protected].
  • 26. Guangzhou Laboratory, Guangzhou, China. [email protected].
  • 27. Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China. [email protected].
  • 28. Department of Microbiology, Queen Mary Hospital, Pokfulam, China. [email protected].
  • 29. Academician Workstation of Hainan Province, Hainan Medical University, Haikou, China. [email protected].
  • 30. Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, China. [email protected].
  • # 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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