IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-48503-x.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-48503-x
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-48503-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Bryan A. Johnson & Xuping Xie & Adam L. Bailey & Birte Kalveram & Kumari G. Lokugamage & Antonio Muruato & Jing Zou & Xianwen Zhang & Terry Juelich & Jennifer K. Smith & Lihong Zhang & Nathen Bopp & C, 2021. "Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis," Nature, Nature, vol. 591(7849), pages 293-299, March.
    2. Shouheng Jin & Xing He & Ling Ma & Zhen Zhuang & Yiliang Wang & Meng Lin & Sihui Cai & Lu Wei & Zheyu Wang & Zhiyao Zhao & Yaoxing Wu & Lin Sun & Chunwei Li & Weihong Xie & Yong Zhao & Zhou Songyang &, 2022. "Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Chao Zhang & Yifan Wang & Yuanfei Zhu & Caixuan Liu & Chenjian Gu & Shiqi Xu & Yalei Wang & Yu Zhou & Yanxing Wang & Wenyu Han & Xiaoyu Hong & Yong Yang & Xueyang Zhang & Tingfeng Wang & Cong Xu & Qin, 2021. "Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Zhikuan Zhang & Norimichi Nomura & Yukiko Muramoto & Toru Ekimoto & Tomoko Uemura & Kehong Liu & Moeko Yui & Nozomu Kono & Junken Aoki & Mitsunori Ikeguchi & Takeshi Noda & So Iwata & Umeharu Ohto & T, 2022. "Structure of SARS-CoV-2 membrane protein essential for virus assembly," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Marko T. Boskovski & Shiaulou Yuan & Nis Borbye Pedersen & Christoffer Knak Goth & Svetlana Makova & Henrik Clausen & Martina Brueckner & Mustafa K. Khokha, 2013. "The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality," Nature, Nature, vol. 504(7480), pages 456-459, December.
    6. Donald J. Benton & Antoni G. Wrobel & Pengqi Xu & Chloë Roustan & Stephen R. Martin & Peter B. Rosenthal & John J. Skehel & Steven J. Gamblin, 2020. "Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion," Nature, Nature, vol. 588(7837), pages 327-330, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Oskar Staufer & Kapil Gupta & Jochen Estebano Hernandez Bücher & Fabian Kohler & Christian Sigl & Gunjita Singh & Kate Vasileiou & Ana Yagüe Relimpio & Meline Macher & Sebastian Fabritz & Hendrik Diet, 2022. "Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Yifan Wang & Caixuan Liu & Chao Zhang & Yanxing Wang & Qin Hong & Shiqi Xu & Zuyang Li & Yong Yang & Zhong Huang & Yao Cong, 2022. "Structural basis for SARS-CoV-2 Delta variant recognition of ACE2 receptor and broadly neutralizing antibodies," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Alexander J. Pak & Alvin Yu & Zunlong Ke & John A. G. Briggs & Gregory A. Voth, 2022. "Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Haisheng Yu & Banghui Liu & Yudi Zhang & Xijie Gao & Qian Wang & Haitao Xiang & Xiaofang Peng & Caixia Xie & Yaping Wang & Peiyu Hu & Jingrong Shi & Quan Shi & Pingqian Zheng & Chengqian Feng & Guofan, 2023. "Somatically hypermutated antibodies isolated from SARS-CoV-2 Delta infected patients cross-neutralize heterologous variants," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Chao Zhang & Caixuan Liu & Jinping Shi & Yalei Wang & Cong Xu & Xiaohua Ye & Qingwei Liu & Xue Li & Weihua Qiao & Yannan Yin & Yao Cong & Zhong Huang, 2022. "Molecular mechanism of antibody neutralization of coxsackievirus A16," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Shelly J. Robertson & Olivia Bedard & Kristin L. McNally & Carl Shaia & Chad S. Clancy & Matthew Lewis & Rebecca M. Broeckel & Abhilash I. Chiramel & Jeffrey G. Shannon & Gail L. Sturdevant & Rebecca , 2023. "Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Qi Zhang & Weichun Tang & Eduardo Stancanelli & Eunkyung Jung & Zulfeqhar Syed & Vijayakanth Pagadala & Layla Saidi & Catherine Z. Chen & Peng Gao & Miao Xu & Ivan Pavlinov & Bing Li & Wenwei Huang & , 2023. "Host heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Zhennan Zhao & Yufeng Xie & Bin Bai & Chunliang Luo & Jingya Zhou & Weiwei Li & Yumin Meng & Linjie Li & Dedong Li & Xiaomei Li & Xiaoxiong Li & Xiaoyun Wang & Junqing Sun & Zepeng Xu & Yeping Sun & W, 2023. "Structural basis for receptor binding and broader interspecies receptor recognition of currently circulating Omicron sub-variants," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    9. Rong Zhu & Daniel Canena & Mateusz Sikora & Miriam Klausberger & Hannah Seferovic & Ahmad Reza Mehdipour & Lisa Hain & Elisabeth Laurent & Vanessa Monteil & Gerald Wirnsberger & Ralph Wieneke & Robert, 2022. "Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Ilyas Khan & Sunan Li & Lihong Tao & Chong Wang & Bowei Ye & Huiyu Li & Xiaoyang Liu & Iqbal Ahmad & Wenqiang Su & Gongxun Zhong & Zhiyuan Wen & Jinliang Wang & Rong-Hong Hua & Ao Ma & Jie Liang & Xia, 2024. "Tubeimosides are pan-coronavirus and filovirus inhibitors that can block their fusion protein binding to Niemann-Pick C1," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. Sun Jin Kim & Zhong Yao & Morgan C. Marsh & Debra M. Eckert & Michael S. Kay & Anna Lyakisheva & Maria Pasic & Aiyush Bansal & Chaim Birnboim & Prabhat Jha & Yannick Galipeau & Marc-André Langlois & J, 2022. "Homogeneous surrogate virus neutralization assay to rapidly assess neutralization activity of anti-SARS-CoV-2 antibodies," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    12. Sebastian Weigang & Jonas Fuchs & Gert Zimmer & Daniel Schnepf & Lisa Kern & Julius Beer & Hendrik Luxenburger & Jakob Ankerhold & Valeria Falcone & Janine Kemming & Maike Hofmann & Robert Thimme & Ch, 2021. "Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    13. Katherine U. Gaynor & Marina Vaysburd & Maximilian A. J. Harman & Anna Albecka & Phillip Jeffrey & Paul Beswick & Guido Papa & Liuhong Chen & Donna Mallery & Brian McGuinness & Katerine Rietschoten & , 2023. "Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    14. Marziah Hashimi & T. Andrew Sebrell & Jodi F. Hedges & Deann Snyder & Katrina N. Lyon & Stephanie D. Byrum & Samuel G. Mackintosh & Dan Crowley & Michelle D. Cherne & David Skwarchuk & Amanda Robison , 2023. "Antiviral responses in a Jamaican fruit bat intestinal organoid model of SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    15. Yang Liu & Xianwen Zhang & Jianying Liu & Hongjie Xia & Jing Zou & Antonio E. Muruato & Sivakumar Periasamy & Chaitanya Kurhade & Jessica A. Plante & Nathen E. Bopp & Birte Kalveram & Alexander Bukrey, 2022. "A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    16. Egon A. Ozer & Lacy M. Simons & Olubusuyi M. Adewumi & Adeola A. Fowotade & Ewean C. Omoruyi & Johnson A. Adeniji & Oluseyi A. Olayinka & Taylor J. Dean & Janet Zayas & Pavan P. Bhimalli & Michelle K., 2022. "Multiple expansions of globally uncommon SARS-CoV-2 lineages in Nigeria," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    17. Xuanming Guo & Jianli Cao & Jian-Piao Cai & Jiayan Wu & Jiangang Huang & Pallavi Asthana & Sheung Kin Ken Wong & Zi-Wei Ye & Susma Gurung & Yijing Zhang & Sheng Wang & Zening Wang & Xin Ge & Hiu Yee K, 2022. "Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    18. Lei Peng & Yingxia Hu & Madeleine C. Mankowski & Ping Ren & Rita E. Chen & Jin Wei & Min Zhao & Tongqing Li & Therese Tripler & Lupeng Ye & Ryan D. Chow & Zhenhao Fang & Chunxiang Wu & Matthew B. Dong, 2022. "Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    19. Wenjuan Dong & Jing Wang & Lei Tian & Jianying Zhang & Erik W. Settles & Chao Qin & Daniel R. Steinken-Kollath & Ashley N. Itogawa & Kimberly R. Celona & Jinhee Yi & Mitchell Bryant & Heather Mead & S, 2023. "Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    20. Daniel Madriz Sørensen & Christian Büll & Thomas D. Madsen & Erandi Lira-Navarrete & Thomas Mandel Clausen & Alex E. Clark & Aaron F. Garretson & Richard Karlsson & Johan F. A. Pijnenborg & Xin Yin & , 2023. "Identification of global inhibitors of cellular glycosylation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48503-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.