An RGD motif on SARS-CoV-2 Spike induces TGF-β signaling and downregulates interferon
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".