tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2023 Dec 12;120(50):e2311913120.
doi: 10.1073/pnas.2311913120. Epub 2023 Dec 7. Integrin α[SUB]5[/SUB]β[SUB]1[/SUB] contributes to cell fusion and inflammation mediated by SARS-CoV-2 spike via RGD-independent interaction
Heng Zhang[SUP] 1 [/SUP], Zhengli Wang[SUP] #[/SUP][SUP] 1 [/SUP], Huong T T Nguyen[SUP] #[/SUP][SUP] 1 [/SUP], Abigail J Watson[SUP] 1 [/SUP], Qifang Lao[SUP] 1 [/SUP], An Li[SUP] 1 [/SUP], Jieqing Zhu[SUP] 1 2 [/SUP]
Affiliations
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[SUB]5[/SUB]β[SUB]1[/SUB], 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[SUB]5[/SUB]β[SUB]1[/SUB] 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[SUB]5[/SUB]β[SUB]1[/SUB] inhibitor ATN-161 or the high-affinity RGD-mimetic inhibitor MK-0429 but requires the participation of α[SUB]5[/SUB] cytoplasmic tail (CT). We detected a direct interaction between α[SUB]5[/SUB]β[SUB]1[/SUB] 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[SUB]5[/SUB]β[SUB]1[/SUB] 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[SUB]5[/SUB] expression or inhibition of the α[SUB]5[/SUB] CT binding protein phosphodiesterase-4D (PDE4D), suggesting the involvement of α[SUB]5[/SUB] 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[SUB]5[/SUB]β[SUB]1[/SUB] and suggest potential targets for antiviral treatment.
Keywords: SARS-CoV-2; cell fusion; inflammation; integrin.
. 2023 Dec 12;120(50):e2311913120.
doi: 10.1073/pnas.2311913120. Epub 2023 Dec 7. Integrin α[SUB]5[/SUB]β[SUB]1[/SUB] contributes to cell fusion and inflammation mediated by SARS-CoV-2 spike via RGD-independent interaction
Heng Zhang[SUP] 1 [/SUP], Zhengli Wang[SUP] #[/SUP][SUP] 1 [/SUP], Huong T T Nguyen[SUP] #[/SUP][SUP] 1 [/SUP], Abigail J Watson[SUP] 1 [/SUP], Qifang Lao[SUP] 1 [/SUP], An Li[SUP] 1 [/SUP], Jieqing Zhu[SUP] 1 2 [/SUP]
Affiliations
- PMID: 38060559
- DOI: 10.1073/pnas.2311913120
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[SUB]5[/SUB]β[SUB]1[/SUB], 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[SUB]5[/SUB]β[SUB]1[/SUB] 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[SUB]5[/SUB]β[SUB]1[/SUB] inhibitor ATN-161 or the high-affinity RGD-mimetic inhibitor MK-0429 but requires the participation of α[SUB]5[/SUB] cytoplasmic tail (CT). We detected a direct interaction between α[SUB]5[/SUB]β[SUB]1[/SUB] 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[SUB]5[/SUB]β[SUB]1[/SUB] 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[SUB]5[/SUB] expression or inhibition of the α[SUB]5[/SUB] CT binding protein phosphodiesterase-4D (PDE4D), suggesting the involvement of α[SUB]5[/SUB] 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[SUB]5[/SUB]β[SUB]1[/SUB] and suggest potential targets for antiviral treatment.
Keywords: SARS-CoV-2; cell fusion; inflammation; integrin.