Evidence map›Paper›PMID 40905682›Full record

ArticleJournal of virology2025

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

Nicholas P Gracie, Anupriya Aggarwal, Rachel Luo, Mitchell Spicer, Sobia Idrees, Caroline L Ashley, Sibel Alca, Timothy Ison, Megan C Steain, Karishma Patel and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of virology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Nicholas P GracieSchool of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0001-9843-367X
Anupriya AggarwalKirby Institute, University of New South Wales, Kensington, New South Wales, Australia.ORCID 0000-0001-8678-0519
Rachel LuoSchool of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia.
Mitchell SpicerRespiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
Sobia IdreesRespiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.ORCID 0000-0001-8512-7593
Caroline L AshleyInfection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0001-8355-8891
Sibel AlcaInfection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0009-0006-5692-8133
Timothy IsonKirby Institute, University of New South Wales, Kensington, New South Wales, Australia.
Megan C SteainInfection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0002-7631-4204
Karishma PatelSchool of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0003-3034-3840
Rezwan SiddiqueeSchool of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0002-7893-3201
Jason K K LowSchool of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0003-0862-0012
Joel P MackaySchool of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia.
Christopher E DenesSchool of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0002-8669-8088
G Gregory NeelySchool of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0002-1957-9732
Alen FaizRespiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.ORCID 0000-0003-1740-3538
Stuart G TurvilleKirby Institute, University of New South Wales, Kensington, New South Wales, Australia.ORCID 0000-0003-1918-5343
Timothy P NewsomeSchool of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia.ORCID 0000-0002-2193-596X

Funding

Drug Discovery Institute, University of SydneySydney Institute of Infectious Diseases
6 · The paper itself

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates canonical cell entry via ACE2 and has also been implicated as an activator of a diverse range of signaling pathways. Here, we present evidence that the RGD (Arg-Gly-Asp) motif within the receptor-binding domain (RBD) of the S1 fragment of the S protein induces TGF-β cytokine expression. RGD peptides are well characterized as ligands for a subset of integrin complexes primarily containing α5 and αV subunits. In this study, we investigate the molecular basis of TGF-β pathway activation by S protein, delivered to cells as recombinant protein, in pseudotyped virus or in virally infected cells. Activation of TGF-β signaling by the S protein requires ACE2 and leads to SMAD3-dependent expression of the pro-fibrotic marker PAI-1. Utilizing pseudotyped viruses, expression of the S protein with a mutated RGD motif abolished TGF-β signaling, as did the RGD antagonist ATN-161, implicating integrin complexes in mediating this response. We show that the S protein RGD motif suppresses IFN-β expression via TGF-β, leading to a disruption in cellular antiviral defenses, consistent with TGF-β's role in immunosuppression. These findings further support the multifunctionality of S protein and provide mechanistic insights into its activity as a virulence factor during infection. IMPORTANCE: 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.

Indexed as

InterferonsOligopeptidesSARS-CoV-2Spike Glycoprotein, CoronavirusTransforming Growth Factor betaAmino Acid MotifsAngiotensin-Converting Enzyme 2AnimalsCOVID-19Down-RegulationHEK293 CellsHumansPlasminogen Activator Inhibitor 1Signal TransductionSmad3 ProteinACE2 protein, humanAngiotensin-Converting Enzyme 2arginyl-glycyl-aspartic acidInterferonsOligopeptidesPlasminogen Activator Inhibitor 1Smad3 ProteinSMAD3 protein, humanSpike Glycoprotein, Coronavirusspike protein, SARS-CoV-2Transforming Growth Factor betacoronavirusCOVID-19IFN-βintegrinsPAI-1RGD (Arg-Gly-Asp)SARS-CoV-2TGF-β

Identifiers

PMID40905682
PMCPMC12456147

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.