Alpha-Soluble NSF Attachment Protein Prevents the Cleavage of the SARS-CoV-2 Spike Protein by Functioning as an Interferon-Upregulated Furin Inhibitor

Jinliang Wang; Jie Luo; Zhiyuan Wen; Xinxin Wang; Lei Shuai; Gongxun Zhong; Chong Wang; Ziruo Sun; Weiye Chen; Jinying Ge; Renqiang Liu; Xijun Wang; Zhigao Bu

doi:10.1128/mbio.02443-21

mBio (Feb 2022)

Alpha-Soluble NSF Attachment Protein Prevents the Cleavage of the SARS-CoV-2 Spike Protein by Functioning as an Interferon-Upregulated Furin Inhibitor

Jinliang Wang,
Jie Luo,
Zhiyuan Wen,
Xinxin Wang,
Lei Shuai,
Gongxun Zhong,
Chong Wang,
Ziruo Sun,
Weiye Chen,
Jinying Ge,
Renqiang Liu,
Xijun Wang,
Zhigao Bu

Affiliations

Jinliang Wang: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Jie Luo: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Zhiyuan Wen: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Xinxin Wang: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Lei Shuai: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Gongxun Zhong: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Chong Wang: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Ziruo Sun: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Weiye Chen: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Jinying Ge: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Renqiang Liu: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Xijun Wang: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China
Zhigao Bu: State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People’s Republic of China

DOI: https://doi.org/10.1128/mbio.02443-21
Journal volume & issue: Vol. 13, no. 1

Abstract

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ABSTRACT Loss of the furin cleavage motif in the SARS-CoV-2 spike protein reduces the virulence and transmission of SARS-CoV-2, suggesting that furin is an attractive antiviral drug target. However, lack of understanding of the regulation of furin activity has largely limited the development of furin-based therapeutic strategies. Here, we find that alpha-soluble NSF attachment protein (α-SNAP), an indispensable component of vesicle trafficking machinery, inhibits the cleavage of SARS-CoV-2 spike protein and other furin-dependent virus glycoproteins. SARS-CoV-2 infection increases the expression of α-SNAP, and overexpression of α-SNAP reduces SARS-CoV-2 infection in cells. We further reveal that α-SNAP is an interferon-upregulated furin inhibitor that inhibits furin function by interacting with its P domain. Our study demonstrates that α-SNAP, in addition to its role in vesicle trafficking, plays an important role in the host defense against furin-dependent virus infection and therefore could be a target for the development of therapeutic options for COVID-19. IMPORTANCE Some key mutations of SARS-CoV-2 spike protein, such as D614G and P681R mutations, increase the transmission or pathogenicity by enhancing the cleavage efficacy of spike protein by furin. Loss of the furin cleavage motif of SARS-CoV-2 spike protein reduces the virulence and transmission, suggesting that furin is an attractive antiviral drug target. However, lack of understanding of the regulation of furin activity has largely limited the development of furin-based therapeutic strategies. Here, we found that in addition to its canonical role in vesicle trafficking, alpha-soluble NSF attachment protein (α-SNAP) plays an important role in the host defense against furin-dependent virus infection. we identified that α-SNAP is a novel interferon-upregulated furin inhibitor and inhibits the cleavage of SARS-CoV-2 spike protein and other furin-dependent virus glycoproteins by interacting with P domain of furin. Our study demonstrates that α-SNAP could be a target for the development of therapeutic options for COVID-19.

Published in mBio

ISSN: 2161-2129 (Print); 2150-7511 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/mbio

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