Host heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation

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, Liqiang Chen, Jian Liu, Hang Xie, Wei Zheng, Yihong Ye

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


SARS-CoV-2 infection causes spike-dependent fusion of infected cells with ACE2 positive neighboring cells, generating multi-nuclear syncytia that are often associated with severe COVID. To better elucidate the mechanism of spike-induced syncytium formation, we combine chemical genetics with 4D confocal imaging to establish the cell surface heparan sulfate (HS) as a critical stimulator for spike-induced cell-cell fusion. We show that HS binds spike and promotes spike-induced ACE2 clustering, forming synapse-like cell-cell contacts that facilitate fusion pore formation between ACE2-expresing and spike-transfected human cells. Chemical or genetic inhibition of HS mitigates ACE2 clustering, and thus, syncytium formation, whereas in a cell-free system comprising purified HS and lipid-anchored ACE2, HS stimulates ACE2 clustering directly in the presence of spike. Furthermore, HS-stimulated syncytium formation and receptor clustering require a conserved ACE2 linker distal from the spike-binding site. Importantly, the cell fusion-boosting function of HS can be targeted by an investigational HS-binding drug, which reduces syncytium formation in vitro and viral infection in mice. Thus, HS, as a host factor exploited by SARS-CoV-2 to facilitate receptor clustering and a stimulator of infection-associated syncytium formation, may be a promising therapeutic target for severe COVID.

Original languageEnglish (US)
Article number5777
JournalNature communications
Issue number1
StatePublished - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023, Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.


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