An RGD motif on SARS-CoV-2 Spike induces TGF-β signaling and downregulates interferon

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes its spike (S) protein for cell entry.
• The S protein is also known to activate various cellular signaling pathways.
• The RGD (Arg-Gly-Asp) motif is a known ligand for integrin complexes.

Purpose of the Study:

• To investigate the molecular mechanisms by which the SARS-CoV-2 S protein activates TGF-β signaling.
• To determine the role of the RGD motif and integrin complexes in this activation.
• To elucidate the impact of S protein-induced TGF-β signaling on cellular antiviral defenses.

Main Methods:

• Utilized recombinant S protein, pseudotyped viruses, and virally infected cells.
• Investigated TGF-β pathway activation, including SMAD3-dependent PAI-1 expression.
• Employed mutated S protein RGD motifs and RGD antagonist ATN-161 to assess the role of integrins.
• Measured IFN-β expression to evaluate antiviral defense disruption.

Main Results:

• The RGD motif in the SARS-CoV-2 S protein's RBD induces TGF-β cytokine expression.
• TGF-β pathway activation requires ACE2 and leads to SMAD3-dependent PAI-1 expression.
• Disruption of the RGD motif or blockade with ATN-161 abolished TGF-β signaling, implicating integrins.
• S protein RGD motif suppresses IFN-β expression via TGF-β, impairing antiviral immunity.

Conclusions:

• The RGD motif in the SARS-CoV-2 S protein is crucial for activating TGF-β signaling through integrin complexes.
• This activation leads to immunosuppression by suppressing IFN-β and hindering antiviral defenses.
• The S protein-integrin signaling axis represents a potential therapeutic target for SARS-CoV-2 infection and long COVID (PASC).