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标题：Integrin activation is an essential component of SARS-CoV-2 infection
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作者：Peter Simons ; Derek A. Rinaldi ; Virginie Bondu 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2021
卷号：11
DOI：10.1038/s41598-021-99893-7
语种：English
出版社：Springer Nature
摘要：SARS-CoV-2 infection depends on binding its spike (S) protein to angiotensin-converting enzyme 2 (ACE2). The S protein expresses an RGD motif, suggesting that integrins may be co-receptors. Here, we UV-inactivated SARS-CoV-2 and fluorescently labeled the envelope membrane with octadecyl rhodamine B (R18) to explore the role of integrin activation in mediating cell entry and productive infection. We used flow cytometry and confocal microscopy to show that SARS-CoV-2 R18 particles engage basal-state integrins. Furthermore, we demonstrate that Mn 2+, which induces integrin extension, enhances cell entry of SARS-CoV-2 R18. We also show that one class of integrin antagonist, which binds to the αI MIDAS site and stabilizes the inactive, closed conformation, selectively inhibits the engagement of SARS-CoV-2 R18 with basal state integrins, but is ineffective against Mn 2+-activated integrins. RGD-integrin antagonists inhibited SARS-CoV-2 R18 binding regardless of integrin activation status. Integrins transmit signals bidirectionally: 'inside-out' signaling primes the ligand-binding function of integrins via a talin-dependent mechanism, and 'outside-in' signaling occurs downstream of integrin binding to macromolecular ligands. Outside-in signaling is mediated by Gα 13. Using cell-permeable peptide inhibitors of talin and Gα 13 binding to the cytoplasmic tail of an integrin's β subunit, we demonstrate that talin-mediated signaling is essential for productive infection.