ArticleNature immunology2021
Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection.
Article in Nature immunology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 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
95 citing papers in PubMed, 144 citations in OpenAlex.
- Understanding protein ISGylation, a multifaceted posttranslational modification.Cell chemical biology · 2026Review
- Nanobodies targeting SARS-CoV-2 papain-like protease exert dual antiviral and anti-inflammatory effects.Journal of virology · 2026Article
- Exploring Key Regulators of Mitochondrial Dynamics and Immune Response in SARS-CoV-2 Infection.Viruses · 2026Article
- Article
- Integrated transcriptomic and metabolomic analysis to elucidate key genes and signaling pathways involved in the promotion of periodontitis by hypertension.Scientific reports · 2026Article
- Immune dysregulation in prolonged Long-COVID: lymphocytes emerge as key mediators of persistent inflammation, exhaustion and cytotoxicity.Journal of translational medicine · 2026Article
- From bats to humans: uncoveringbioRxiv : the preprint server for biology · 2026Article
- Proteomics and tracer metabolomics link GAPDH ISGylation to glycolytic control.Genome biology · 2026Article
- Extracellular Lipopolysaccharide Triggers the Release of Unconjugated Interferon-Stimulated Gene 15 (ISG15) Protein from Macrophages via Type-I Interferon/Caspase-4/Gasdermin-D Pathway.Pathogens (Basel, Switzerland) · 2026Article
- A murine coronavirus infection platform identifies proviral and proinflammatory activities of SARS-CoV-2 accessory protein 7a.Journal of virology · 2026Article
- Cytokine storm.Nature reviews. Disease primers · 2026Review
- METTL3 abrogation promotes glioma progression through regulating the ISG15-FASN axis-mediated lipid metabolism in macrophages.Nature communications · 2026Article
- Interferon-induced protein ISG15 in the central nervous system, quo vadis?FEBS letters · 2025Review
- Structural and functional insights into Ubl domain-mediated regulation of SARS-CoV-2 PLpro.Biology direct · 2025Article
- Remodelled cholesteryl ester enriched lipid droplets fuel flavivirus morphogenesis.bioRxiv : the preprint server for biology · 2025Article
- Immune signatures of SARS-CoV-2 infection resolution in human lung tissues.PLoS pathogens · 2025Article
- ISG-15, beyond its functions in the cell: a mini review.Cellular and molecular life sciences : CMLS · 2025Review
- Porcine reproductive and respiratory syndrome virus NSP5 exploited UBE2L6 to promote viral replication via antagonising host RLRs and ISGylation.Veterinary research · 2025Article
- Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids.Nature communications · 2025Article
- ISG15 as a Potent Immune Adjuvant in MVA-Based Vaccines Against Zika Virus and SARS-CoV-2.Vaccines · 2025Article
35 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 8 institutions in 6 countries.
Funding
Abstract
Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.
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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.