ArticlePLoS pathogens2023
Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection.
Article in PLoS pathogens, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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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.
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Who cites it
28 citing papers in PubMed, 31 citations in OpenAlex.
- Secreted ORF8 reprograms macrophages to enhance SARS-CoV-2 infection of lung epithelial cells.Science advances · 2026Article
- ZDHHC18-Mediated Palmitoylation of ORF3a Promotes SARS-CoV-2 Pathogenesis by Antagonizing TRIM16-Mediated Ubiquitination and Proteasomal Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Secreted Nonstructural Protein 3 is a Pathogenic Determinant of Orbivirus.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Secreted ORF8 reprograms macrophages to enhance SARS-CoV-2 infection of lung epithelial cells.bioRxiv : the preprint server for biology · 2026Article
- Article
- Unlocking the black box: multimodal imaging and quantitative analysis of plant vesicular trafficking.Advanced biotechnology · 2026Review
- Regulation of virion production by the ORF8 signal peptide across SARS-CoV-2 variants.bioRxiv : the preprint server for biology · 2026Article
- A murine coronavirus infection platform identifies proviral and proinflammatory activities of SARS-CoV-2 accessory protein 7a.Journal of virology · 2026Article
- The "cytokine storm" in infection and sepsis: win the battle but lose the war.Military Medical Research · 2026Review
- SARS-CoV-2 ORF8: an accessory protein at the interface of immune evasion and inflammation.Frontiers in immunology · 2026Review
- CROI 2025: Acute and Postacute COVID-19.Topics in antiviral medicine · 2025Article
- The Recurring Loss of ORF8 Secretion in Dominant SARS-CoV-2 Variants.International journal of molecular sciences · 2025Article
- Review
- Yip1 interacting factor homolog B mediates the unconventional secretion of ORF8 during SARS-CoV-2 infection.iScience · 2025Article
- Febuxostat may decrease the incidence of COVID-19 infection among patients with gout: a retrospective cohort study.Frontiers in pharmacology · 2025Article
- Non-spike protein inhibition of SARS-CoV-2 by natural products through the key mediator protein ORF8.Molecular biology research communications · 2025Article
- Hidden players of COVID-19: the evolving roles of SARS-CoV-2 accessory proteins.Frontiers in immunology · 2025Review
- Coronavirus envelope protein activates TMED10-mediated unconventional secretion of inflammatory factors.Nature communications · 2024Article
- Genomic surveillance and vaccine response to the dominant SARS-CoV-2 XBB lineage in Rio Grande do Sul.Scientific reports · 2024Article
- Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution.Nature communications · 2024Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 4 countries.
Funding
Abstract
Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS-CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. Conventionally secreted ORF8 is glycosylated and loses the ability to recognize interleukin 17 receptor A of macrophages, possibly due to the steric hindrance imposed by N-glycosylation at Asn78. However, unconventionally secreted ORF8 does not undergo glycosylation without experiencing the ER-Golgi trafficking, thereby activating the downstream NF-κB signaling pathway and facilitating a burst of cytokine release. Furthermore, we show that ORF8 deletion in SARS-CoV-2 attenuates inflammation and yields less lung lesions in hamsters. Our data collectively highlights a role of ORF8 protein in the development of cytokine storms during SARS-CoV-2 infection.
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Registered trials
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 OpenQuestion graph.