Zhang H, Wang Z, Nguyen HTT, Watson AJ, Lao Q, Li A, Zhu J

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infects host cells by engaging its spike (S) protein with human ACE2 receptor. Recent studies suggest the involvement of integrins in SARS-CoV-2 infection through interaction with the S protein, but the underlying mechanism is not well understood. This study investigated the ...

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role of integrin ?5?1, which recognizes the Arg-Gly-Asp (RGD) motif in its physiological ligands, in S-mediated virus entry and cell-cell fusion. Our results showed that ?5?1 does not directly contribute to S-mediated cell entry, but it enhances S-mediated cell-cell fusion in collaboration with ACE2. This effect cannot be inhibited by the putative ?5?1 inhibitor ATN-161 or the high-affinity RGD-mimetic inhibitor MK-0429 but requires the participation of ?5 cytoplasmic tail (CT). We detected a direct interaction between ?5?1 and the S protein, but this interaction does not rely on the RGD-containing receptor binding domain of the S1 subunit of the S protein. Instead, it involves the S2 subunit of the S protein and ?5?1 homo-oligomerization. Furthermore, we found that the S protein induces inflammatory responses in human endothelial cells, characterized by NF-?B activation, gasdermin D cleavage, and increased secretion of proinflammatory cytokines IL-6 and IL-1?. These effects can be attenuated by the loss of ?5 expression or inhibition of the ?5 CT binding protein phosphodiesterase-4D (PDE4D), suggesting the involvement of ?5 CT and PDE4D pathway. These findings provide molecular insights into the pathogenesis of SARS-CoV-2 mediated by a nonclassical RGD-independent ligand-binding and signaling function of integrin ?5?1 and suggest potential targets for antiviral treatment.

Date: Dec. 12, 2023

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