Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-99893-7
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Funding
- National Center for Advancing Translational Sciences, National Institutes of Health [UL1TR001449]
- NIH [R35GM-126934, NIH P30CA118100]
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SARS-CoV-2 infection relies on the binding of its spike protein to ACE2, with integrins potentially acting as co-receptors. Integrins play a crucial role in mediating cell entry and infection, with talin-mediated signaling being essential for the productive infection process.
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 Mn2+, 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 alpha I 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 Mn2+-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 G alpha(13). Using cell-permeable peptide inhibitors of talin and G alpha(13) binding to the cytoplasmic tail of an integrin's beta subunit, we demonstrate that talin-mediated signaling is essential for productive infection.
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