Coronaviruses exploit a host cysteine-aspartic protease for replication

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, Kin Shing Lee, Cuiting Luo, Jian-Piao Cai, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Anna Jinxia Zhang, Shuofeng Yuan, Ko-Yung Sit, Dominic Chi-Chung Foo, Wing-Kuk Au, Kenneth Kak-Yuen Wong, Jie Zhou, Kin-Hang Kok, Dong-Yan Jin, Jasper Fuk-Woo Chan () and Kwok-Yung Yuen ()
Additional contact information
Hin Chu: The University of Hong Kong
Yuxin Hou: The University of Hong Kong
Dong Yang: The University of Hong Kong
Lei Wen: The University of Hong Kong
Huiping Shuai: The University of Hong Kong
Chaemin Yoon: The University of Hong Kong
Jialu Shi: The University of Hong Kong
Yue Chai: The University of Hong Kong
Terrence Tsz-Tai Yuen: The University of Hong Kong
Bingjie Hu: The University of Hong Kong
Cun Li: The University of Hong Kong
Xiaoyu Zhao: The University of Hong Kong
Yixin Wang: The University of Hong Kong
Xiner Huang: The University of Hong Kong
Kin Shing Lee: The University of Hong Kong
Cuiting Luo: The University of Hong Kong
Jian-Piao Cai: The University of Hong Kong
Vincent Kwok-Man Poon: The University of Hong Kong
Chris Chung-Sing Chan: The University of Hong Kong
Anna Jinxia Zhang: The University of Hong Kong
Shuofeng Yuan: The University of Hong Kong
Ko-Yung Sit: The University of Hong Kong
Dominic Chi-Chung Foo: The University of Hong Kong
Wing-Kuk Au: The University of Hong Kong
Kenneth Kak-Yuen Wong: The University of Hong Kong
Jie Zhou: The University of Hong Kong
Kin-Hang Kok: The University of Hong Kong
Dong-Yan Jin: Hong Kong Science and Technology Park
Jasper Fuk-Woo Chan: The University of Hong Kong
Kwok-Yung Yuen: The University of Hong Kong

Nature, 2022, vol. 609, issue 7928, 785-792

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05148-4

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