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

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an ongoing public health challenge as a cause of acute illness and post-acute sequelae of COVID-19 (PASC, or long COVID). Our study identifies the RGD integrin-binding motif in the spike (S) protein as central to the cellular resp...

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Published in:Journal of virology Vol. 99; no. 9; p. e0043525
Main Authors: Gracie, Nicholas P., Aggarwal, Anupriya, Luo, Rachel, Spicer, Mitchell, Idrees, Sobia, Ashley, Caroline L., Alca, Sibel, Ison, Timothy, Steain, Megan C., Patel, Karishma, Siddiquee, Rezwan, Low, Jason K. K., Mackay, Joel P., Denes, Christopher E., Neely, G. Gregory, Faiz, Alen, Turville, Stuart G., Newsome, Timothy P.
Format: Journal Article
Language:English
Published: United States American Society for Microbiology 23.09.2025
Subjects:
Amino Acid Motifs
Angiotensin-Converting Enzyme 2 - metabolism
Animals
coronavirus
COVID-19
COVID-19 - metabolism
COVID-19 - virology
Down-Regulation
Editor’s Pick
HEK293 Cells
Humans
integrins
Interferons - metabolism
Oligopeptides - metabolism
Plasminogen Activator Inhibitor 1 - genetics
Plasminogen Activator Inhibitor 1 - metabolism
RGD (Arg-Gly-Asp)
SARS-CoV-2
SARS-CoV-2 - metabolism
Signal Transduction
Smad3 Protein - metabolism
Spike Glycoprotein, Coronavirus - chemistry
Spike Glycoprotein, Coronavirus - genetics
Spike Glycoprotein, Coronavirus - metabolism
TGF-β
Transforming Growth Factor beta - metabolism
Virology
Virus-Cell Interactions
COVID-19
SARS-CoV-2
integrins
IFN-β
RGD (Arg-Gly-Asp)
PAI-1
TGF-β
coronavirus
ISSN:0022-538X, 1098-5514, 1098-5514
Online Access:Get full text
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Summary:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an ongoing public health challenge as a cause of acute illness and post-acute sequelae of COVID-19 (PASC, or long COVID). Our study identifies the RGD integrin-binding motif in the spike (S) protein as central to the cellular response to SARS-CoV-2, leading to the expression of the pleiotropic cytokine TGF-β and disabling of antiviral immunity. This work further supports the S protein-to-integrin complex signaling axis as a potential therapeutic target. The RGD motif might also be a valid target for treating PASC given the increasing body of evidence implicating the presence of persistent S protein in the etiology of this disease.
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ISSN:0022-538X
1098-5514
1098-5514
DOI:10.1128/jvi.00435-25