ArticlePLoS pathogens2014
The PDZ-binding motif of severe acute respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis.
Article in PLoS pathogens, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04511819 (A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Losmapimod in Adult Subjects With COVID-19), which is not on this map. Cited by 161 papers, 1 of them a synthesis that pooled it.
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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.
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.
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Losmapimod in Adult Subjects With COVID-19 (LOSVID STUDY)
Who cites it
161 citing papers in PubMed, 1 synthesis or guideline pooled it, 260 citations in OpenAlex.
- The Reassessed Potential of SARS-CoV-2 Attenuation for COVID-19 Vaccine Development-A Systematic Review.Viruses · 2022Pooled it
- Structural insights into an aptainhibitor of the SARS-CoV-2 E protein using molecular docking, molecular dynamics, and biophysical analyses.Molecular therapy. Nucleic acids · 2026Article
- PEDV envelope protein promotes viral replication by remodeling host iron homeostasis via the TRIM28-KLF15-FPN axis.Journal of virology · 2026Article
- Intrinsically dominant conformational diversity in PDZ1 within the tandem PDZ1-PDZ2 of human syntenin-1 underlined by crystal structures.Protein science : a publication of the Protein Society · 2026Article
- SARS-CoV-2 envelope protein mitochondrial localization reveals host metabolic disruption.The Journal of biological chemistry · 2026Article
- Interaction of coronavirus E protein with BRD2 plays important regulatory roles in viral replication and induction of pro-inflammatory response.Journal of virology · 2026Article
- C-terminus-outward orientation of SARS-CoV-2 envelope proteins on viral capsid enables a novel virus-cell interaction pathway.Frontiers in cellular and infection microbiology · 2026Article
- HTRF-based identification of small molecules targeting SARS-CoV-2 E protein interaction with ZO-1 PDZ2.Scientific reports · 2025Article
- Evolutionarily divergent nidovirus with an exceptionally large genome identified in Pacific oysters undergoing mass mortality.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Inhibitors of Tax1-PDZ Interactions Block HTLV-1 Viral Transmission by Changing EV Composition.Journal of extracellular vesicles · 2025Article
- The SARS-CoV-2 envelope PDZ binding motif acts as a virulence factor disrupting host's epithelial cell-cell junctions.Cellular & molecular biology letters · 2025Article
- Advances in Viroporin Function and Structure: A Comparative Analysis of Alphavirus 6K with Well-Characterized Viroporins.Viruses · 2025Review
- Phosphorylation Modifications and Their Role in Viral Pneumonia: Mechanisms and Therapeutic Implications.Infection and drug resistance · 2025Review
- Molecular Dynamics Simulation of SARS-CoV-2 E Ion Channel: The Study of Lone Protein and its Conformational Changes in Complex with Potential Cage Inhibitors.Current computer-aided drug design · 2025Article
- IGSF1: a biomarker for predicting prognosis, immunotherapy response, and drug candidates in COVID-19 combined hepatocellular carcinoma.Discover oncology · 2024Article
- SARS-CoV-2 envelope protein alters calcium signaling via SERCA interactions.Scientific reports · 2024Article
- Membrane Activity and Viroporin Assembly for the SARS-CoV-2 E Protein Are Regulated by Cholesterol.Biomolecules · 2024Article
- Article
- Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models.Zoological research · 2024Review
- ER-export and ARFRP1/AP-1-dependent delivery of SARS-CoV-2 Envelope to lysosomes controls late stages of viral replication.Science advances · 2024Article
101 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
A recombinant severe acute respiratory syndrome coronavirus (SARS-CoV) lacking the envelope (E) protein is attenuated in vivo. Here we report that E protein PDZ-binding motif (PBM), a domain involved in protein-protein interactions, is a major determinant of virulence. Elimination of SARS-CoV E protein PBM by using reverse genetics caused a reduction in the deleterious exacerbation of the immune response triggered during infection with the parental virus and virus attenuation. Cellular protein syntenin was identified to bind the E protein PBM during SARS-CoV infection by using three complementary strategies, yeast two-hybrid, reciprocal coimmunoprecipitation and confocal microscopy assays. Syntenin redistributed from the nucleus to the cell cytoplasm during infection with viruses containing the E protein PBM, activating p38 MAPK and leading to the overexpression of inflammatory cytokines. Silencing of syntenin using siRNAs led to a decrease in p38 MAPK activation in SARS-CoV infected cells, further reinforcing their functional relationship. Active p38 MAPK was reduced in lungs of mice infected with SARS-CoVs lacking E protein PBM as compared with the parental virus, leading to a decreased expression of inflammatory cytokines and to virus attenuation. Interestingly, administration of a p38 MAPK inhibitor led to an increase in mice survival after infection with SARS-CoV, confirming the relevance of this pathway in SARS-CoV virulence. Therefore, the E protein PBM is a virulence domain that activates immunopathology most likely by using syntenin as a mediator of p38 MAPK induced inflammation.
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