Receptor-binding domain of SARS-CoV-2 is a functional αv-integrin agonist

Area of Science:

• Molecular biology
• Virology
• Cell biology

Background:

• SARS-CoV-2 spike protein's S1 region contains a K403R mutation in the receptor-binding domain (RBD).
• This mutation creates an RGD adhesion motif, similar to extracellular matrix proteins like fibronectin.
• Integrins are cell surface receptors that bind extracellular matrix proteins and mediate cell adhesion and signaling.

Purpose of the Study:

• To investigate if the SARS-CoV-2 S1-RBD can bind to cell surface integrins.
• To compare the integrin-binding and signaling capabilities of S1-RBD with fibronectin.
• To explore the potential role of S1-RBD-integrin interactions in SARS-CoV-2 pathogenesis.

Main Methods:

• Assessed S1-RBD binding to fibronectin-null cells and primary human airway epithelial cells.
• Utilized microparticle adhesion assays and surface plasmon resonance (SPR) to study S1-RBD-integrin interactions.
• Investigated downstream signaling events including cell spreading, focal adhesion formation, and protein phosphorylation.

Main Results:

• S1-RBD supported cell adhesion in a cation-dependent and RGD-dependent manner, specifically involving αvβ3 and αvβ6 integrins.
• S1-RBD binding triggered cell spreading, focal adhesion formation, and actin organization, mimicking fibronectin's effects.
• S1-RBD activated key signaling molecules like FAK, Src, paxillin, and Akt, promoting cell proliferation.

Conclusions:

• The RGD motif in SARS-CoV-2 S1-RBD acts as an αv-selective integrin agonist.
• Cell surface integrins can functionally respond to the viral spike protein.
• S1-RBD-mediated integrin activation may contribute to SARS-CoV-2 pathogenesis and long COVID symptoms.