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

Author

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  • Shengjun Wang

    (Sun Yat-sen University
    University of Health and Rehabilitation Sciences)

  • 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
    Foshan Institute for Food and Drug Control)

  • 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
    Guangzhou Eighth People’s Hospital of Guangzhou Medical University
    Bio-island
    Southern University of Science and Technology)

  • Yang Mao

    (Sun Yat-sen University
    Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and Research)

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.

Suggested Citation

  • 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 Wa, 2024. "Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48503-x
    DOI: 10.1038/s41467-024-48503-x
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