Integrin α 5 β 1 contributes to cell fusion and inflammation mediated by SARS-CoV-2 spike via RGD-independent interaction.
Heng ZhangZhengli WangHuong T T NguyenAbigail J WatsonQifang LaoAn LiJieqing ZhuPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
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 role of integrin α 5 β 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 α 5 β 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 α 5 β 1 inhibitor ATN-161 or the high-affinity RGD-mimetic inhibitor MK-0429 but requires the participation of α 5 cytoplasmic tail (CT). We detected a direct interaction between α 5 β 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 α 5 β 1 homo-oligomerization. Furthermore, we found that the S protein induces inflammatory responses in human endothelial cells, characterized by NF-κB activation, gasdermin D cleavage, and increased secretion of proinflammatory cytokines IL-6 and IL-1β. These effects can be attenuated by the loss of α 5 expression or inhibition of the α 5 CT binding protein phosphodiesterase-4D (PDE4D), suggesting the involvement of α 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 α 5 β 1 and suggest potential targets for antiviral treatment.
Keyphrases
- sars cov
- binding protein
- respiratory syndrome coronavirus
- endothelial cells
- single cell
- cell therapy
- protein protein
- physical activity
- amino acid
- coronavirus disease
- oxidative stress
- risk assessment
- signaling pathway
- transcription factor
- immune response
- bone marrow
- angiotensin ii
- climate change
- pi k akt
- high resolution
- cell cycle arrest
- cell migration
- lps induced
- dna binding