TY - JOUR
T1 - Host heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation
AU - Zhang, Qi
AU - Tang, Weichun
AU - Stancanelli, Eduardo
AU - Jung, Eunkyung
AU - Syed, Zulfeqhar
AU - Pagadala, Vijayakanth
AU - Saidi, Layla
AU - Chen, Catherine Z.
AU - Gao, Peng
AU - Xu, Miao
AU - Pavlinov, Ivan
AU - Li, Bing
AU - Huang, Wenwei
AU - Chen, Liqiang
AU - Liu, Jian
AU - Xie, Hang
AU - Zheng, Wei
AU - Ye, Yihong
N1 - Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85171563305&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85171563305&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-41453-w
DO - 10.1038/s41467-023-41453-w
M3 - Article
C2 - 37723160
AN - SCOPUS:85171563305
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5777
ER -