{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T20:26:11Z","timestamp":1785529571580,"version":"3.56.0"},"reference-count":112,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Sydney Institute of Infectious Diseases"},{"name":"Drug Discovery Institute, University of Sydney"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2025,9,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>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-\u03b2 cytokine expression. RGD peptides are well characterized as ligands for a subset of integrin complexes primarily containing \u03b15 and \u03b1V subunits. In this study, we investigate the molecular basis of TGF-\u03b2 pathway activation by S protein, delivered to cells as recombinant protein, in pseudotyped virus or in virally infected cells. Activation of TGF-\u03b2 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-\u03b2 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-\u03b2 expression via TGF-\u03b2, leading to a disruption in cellular antiviral defenses, consistent with TGF-\u03b2\u2019s 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>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-\u03b2 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00435-25","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T13:00:24Z","timestamp":1756990824000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["An RGD motif on SARS-CoV-2 Spike induces TGF-\u03b2 signaling and downregulates interferon"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9843-367X","authenticated-orcid":true,"given":"Nicholas P.","family":"Gracie","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0384j8v12","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life and Environmental Sciences, The University of Sydney","place":["Camperdown, 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S Sun H Bu X Wan G. 2020. 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