State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China.
mBio. 2022 Feb 22;13(1):e0244321. doi: 10.1128/mbio.02443-21. Epub 2022 Jan 11.
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. 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.
新冠病毒 S 蛋白中弗林蛋白酶裂解位点缺失会降低病毒的毒力和传播能力，这表明弗林蛋白酶是一种有吸引力的抗病毒药物靶点。然而，对弗林蛋白酶活性调节的认识不足在很大程度上限制了基于弗林蛋白酶的治疗策略的发展。在这里，我们发现 α-可溶性 NSF 附着蛋白（α-SNAP），一种囊泡运输机制所必需的成分，会抑制新冠病毒 S 蛋白和其他依赖弗林蛋白酶的病毒糖蛋白的裂解。新冠病毒感染会增加 α-SNAP 的表达，而过表达 α-SNAP 会降低细胞中的新冠病毒感染。我们进一步揭示，α-SNAP 是一种干扰素上调的弗林蛋白酶抑制剂，通过与弗林蛋白酶的 P 结构域相互作用来抑制其功能。我们的研究表明，α-SNAP 除了在囊泡运输中的作用外，还在宿主防御依赖弗林蛋白酶的病毒感染中发挥重要作用，因此它可能成为开发针对 COVID-19 的治疗选择的靶点。新冠病毒 S 蛋白的一些关键突变，如 D614G 和 P681R 突变，通过增强 S 蛋白的弗林蛋白酶裂解效率来增加病毒的传播或致病性。新冠病毒 S 蛋白弗林蛋白酶裂解位点缺失会降低病毒的毒力和传播能力，这表明弗林蛋白酶是一种有吸引力的抗病毒药物靶点。然而，对弗林蛋白酶活性调节的认识不足在很大程度上限制了基于弗林蛋白酶的治疗策略的发展。在这里，我们发现除了其在囊泡运输中的典型作用外，α-可溶性 NSF 附着蛋白（α-SNAP）在宿主防御依赖弗林蛋白酶的病毒感染方面也发挥着重要作用。我们鉴定出 α-SNAP 是一种新型干扰素上调的弗林蛋白酶抑制剂，通过与弗林蛋白酶的 P 结构域相互作用来抑制新冠病毒 S 蛋白和其他依赖弗林蛋白酶的病毒糖蛋白的裂解。我们的研究表明，α-SNAP 可能成为开发 COVID-19 治疗选择的靶点。
