ArticleeLife2023
The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 66 citations in OpenAlex.
- The accessory protein ORF3a hijacks the CLCC1 chloride channel to disrupt ER homeostasis in betacoronavirus pathogenesis.Cell discovery · 2026Article
- SARS-CoV-2 Delta variant-specific ORF3a mutations destabilize lysosomal homeostasis to trigger lysosomal damage-mediated cell death.Communications biology · 2026Article
- SARS-CoV-2 ORF3a blocks lysosomal cholesterol egress by disrupting VPS39-regulated NPC2 trafficking and BMP metabolism.Cell reports · 2026Article
- Targeting SARS-CoV-2 Structural and Accessory Proteins: Emerging Opportunities for Small-Molecule Coronavirus Antivirals.Pharmaceutics · 2026Review
- BST-2 inhibits SARS-CoV-2 egress at intracellular membranes and is neutralized by ORF7a.Scientific reports · 2026Article
- SARS-CoV-2 enhances lysosomal exocytosis and deacidifies lysosomes to facilitate viral release.mLife · 2026Article
- Computational modelling of the equine arteritis virus GP5/M Dimer: Implications for immune evasion and virulence.PloS one · 2026Article
- Structural and Computational Insights into the Attenuated Innate Immune Recognition of the SARS-CoV-2 N15 Lineage, an Early-Pandemic Variant.Computational and structural biotechnology journal · 2026Article
- COVID-19 and Lung Cancer Interactions: A Literature Review.Medical sciences (Basel, Switzerland) · 2025Review
- TGF-β inhibitor SB431542 suppresses SARS-CoV-2 replication through multistep inhibition.Journal of virology · 2025Article
- SARS-CoV-2 ORF3a blocks lysosomal cholesterol egress by disrupting VPS39-regulated NPC2 trafficking and BMP metabolism.bioRxiv : the preprint server for biology · 2025Article
- Article
- A metastasis-associated pannexin-1 mutant (Panx1The FEBS journal · 2025Article
- SARS-CoV-2 accessory proteins ORF3a and ORF6 alter the miRNome of human lung epithelial cells.Molecular biology reports · 2025Article
- SARS-CoV-2 ORF3a drives dynamic dense body formation for optimal viral infectivity.Nature communications · 2025Article
- SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19.Cell reports · 2025Article
- Article
- A live attenuated SARS-CoV-2 vaccine constructed by dual inactivation of NSP16 and ORF3a.EBioMedicine · 2025Article
- Bid Protein: A Participant in the Apoptotic Network with Roles in Viral Infections.International journal of molecular sciences · 2025Review
- Subcellular localization of SARS-CoV-2 E and 3a proteins along the secretory pathway.Journal of molecular histology · 2025Article
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
The severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) and SARS-CoV-1 accessory protein Orf3a colocalizes with markers of the plasma membrane, endocytic pathway, and Golgi apparatus. Some reports have led to annotation of both Orf3a proteins as viroporins. Here, we show that neither SARS-CoV-2 nor SARS-CoV-1 Orf3a form functional ion conducting pores and that the conductances measured are common contaminants in overexpression and with high levels of protein in reconstitution studies. Cryo-EM structures of both SARS-CoV-2 and SARS-CoV-1 Orf3a display a narrow constriction and the presence of a positively charged aqueous vestibule, which would not favor cation permeation. We observe enrichment of the late endosomal marker Rab7 upon SARS-CoV-2 Orf3a overexpression, and co-immunoprecipitation with VPS39. Interestingly, SARS-CoV-1 Orf3a does not cause the same cellular phenotype as SARS-CoV-2 Orf3a and does not interact with VPS39. To explain this difference, we find that a divergent, unstructured loop of SARS-CoV-2 Orf3a facilitates its binding with VPS39, a HOPS complex tethering protein involved in late endosome and autophagosome fusion with lysosomes. We suggest that the added loop enhances SARS-CoV-2 Orf3a's ability to co-opt host cellular trafficking mechanisms for viral exit or host immune evasion.
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