1. Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity.
- Author
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Wang, Shengjun, Ran, Wei, Sun, Lingyu, Fan, Qingchi, Zhao, Yuanqi, Wang, Bowen, Yang, Jinghong, He, Yuqi, Wu, Ying, Wang, Yuanyuan, Chen, Luoyi, Chuchuay, Arpaporn, You, Yuyu, Zhu, Xinhai, Wang, Xiaojuan, Chen, Ye, Wang, Yanqun, Chen, Yao-Qing, Yuan, Yanqiu, and Zhao, Jincun
- Subjects
VIRAL proteins ,SARS-CoV-2 Omicron variant ,SARS-CoV-2 Delta variant ,SARS-CoV-2 ,GLYCOSYLATION - Abstract
The multibasic furin cleavage site at the S1/S2 boundary of the spike protein is a hallmark of SARS-CoV-2 and plays a crucial role in viral infection. However, the mechanism underlying furin activation and its regulation remain poorly understood. Here, we show that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the furin cleavage site of the SARS-CoV-2 spike protein, which inhibit furin processing, suppress the incorporation of the spike protein into virus-like-particles and affect viral infection. Mechanistic analysis reveals that the assembly of the spike protein into virus-like particles relies on interactions between the furin-cleaved spike protein and the membrane protein of SARS-CoV-2, suggesting a possible mechanism for furin activation. Interestingly, mutations in the spike protein of the alpha and delta variants of the virus confer resistance against glycosylation by GalNAc-T3 and T7. In the omicron variant, additional mutations reverse this resistance, making the spike protein susceptible to glycosylation in vitro and sensitive to GalNAc-T3 and T7 expression in human lung cells. Our findings highlight the role of glycosylation as a defense mechanism employed by host cells against SARS-CoV-2 and shed light on the evolutionary interplay between the host and the virus. Here, the authors show that GalNAc-T3 and T7 regulate furin cleavage of the SARS-CoV-2 spike protein via O-glycosylation. This influences viral assembly and infection, highlighting glycosylation as a host defense mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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