Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity

Shengjun Wang, Wei Ran, Lingyu Sun, Qingchi Fan, Yuanqi Zhao, Bowen Wang, Jinghong Yang, Yuqi He, Ying Wu, Yuanyuan Wang, Luoyi Chen, Arpaporn Chuchuay, Yuyu You, Xinhai Zhu, Xiaojuan Wang, Ye Chen, Yanqun Wang, Yao-Qing Chen, Yanqiu Yuan (), Jincun Zhao () and Yang Mao ()
Additional contact information
Shengjun Wang: Sun Yat-sen University
Wei Ran: The First Affiliated Hospital of Guangzhou Medical University
Lingyu Sun: Sun Yat-sen University
Qingchi Fan: Sun Yat-sen University
Yuanqi Zhao: Sun Yat-sen University
Bowen Wang: Northwest University
Jinghong Yang: The First Affiliated Hospital of Guangzhou Medical University
Yuqi He: Sun Yat-sen University
Ying Wu: Sun Yat-sen University
Yuanyuan Wang: Shenzhen Campus of Sun Yat-sen University
Luoyi Chen: Sun Yat-sen University
Arpaporn Chuchuay: Sun Yat-sen University
Yuyu You: Sun Yat-sen University
Xinhai Zhu: Sun Yat-sen University
Xiaojuan Wang: Sun Yat-sen University
Ye Chen: Fujian Agriculture and Forestry University
Yanqun Wang: The First Affiliated Hospital of Guangzhou Medical University
Yao-Qing Chen: Shenzhen Campus of Sun Yat-sen University
Yanqiu Yuan: Sun Yat-sen University
Jincun Zhao: The First Affiliated Hospital of Guangzhou Medical University
Yang Mao: Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48503-x

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