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Published on: November 8, 2024
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Integrin α5β1 contributes to cell fusion and inflammation mediated by SARS-CoV-2 spike via RGD-independent
Heng Zhang1, Zhengli Wang1, Huong T T Nguyen1
1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI 53226.
Summary
Integrin α5β1 enhances SARS-CoV-2 cell-cell fusion via its cytoplasmic tail, not direct entry, and promotes inflammation through the PDE4D pathway. This reveals nonclassical integrin functions for potential antiviral targets.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses its spike (S) protein to bind ACE2 receptors for cell entry.
- Integrins, particularly α5β1, have been implicated in SARS-CoV-2 infection, but their precise roles and mechanisms remain unclear.
- Understanding integrin involvement is crucial for developing novel antiviral strategies.
Purpose of the Study:
- To investigate the specific role of integrin α5β1 in SARS-CoV-2 S protein-mediated cell entry and cell-cell fusion.
- To elucidate the molecular mechanisms underlying α5β1 interaction with the SARS-CoV-2 S protein.
- To examine the contribution of α5β1 to SARS-CoV-2-induced inflammatory responses.
Main Methods:
- Utilized cell-based assays to assess S protein-mediated viral entry and cell-cell fusion.
- Employed RGD-mimetic inhibitors and genetic manipulation to study α5β1 function.
- Investigated protein-protein interactions using co-immunoprecipitation and Western blotting.
- Analyzed inflammatory markers, including NF-κB activation, gasdermin D cleavage, and cytokine secretion (IL-6, IL-1β).
Main Results:
- Integrin α5β1 does not directly mediate SARS-CoV-2 cell entry but enhances S protein-mediated cell-cell fusion with ACE2.
- This enhancement is independent of the RGD motif and requires the α5 cytoplasmic tail (CT), not RGD-inhibitors.
- A direct interaction occurs between the S2 subunit of the S protein and α5β1, involving α5β1 homo-oligomerization.
- SARS-CoV-2 S protein triggers inflammatory responses (NF-κB activation, IL-6/IL-1β release) in endothelial cells.
- These inflammatory effects are attenuated by α5 knockdown or inhibition of α5 CT-binding protein PDE4D.
Conclusions:
- Integrin α5β1 plays a critical role in SARS-CoV-2 cell-cell fusion through a nonclassical, RGD-independent mechanism involving its cytoplasmic tail.
- The α5β1-S protein interaction contributes to SARS-CoV-2-induced inflammation via the α5 CT-PDE4D pathway.
- These findings highlight novel roles for integrin α5β1 in viral pathogenesis and suggest potential therapeutic targets for COVID-19 treatment.
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