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Altered ISGylation drives aberrant macrophage-dependent immune responses during SARS-CoV-2 infection.
Munnur, Deeksha; Teo, Qiwen; Eggermont, Denzel; Lee, Horace H Y; Thery, Fabien; Ho, Julian; van Leur, Sophie Wilhelmina; Ng, Wilson W S; Siu, Lewis Y L; Beling, Antje; Ploegh, Hidde; Pinto-Fernandez, Adan; Damianou, Andreas; Kessler, Benedikt; Impens, Francis; Mok, Chris Ka Pun; Sanyal, Sumana.
  • Munnur D; Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, UK.
  • Teo Q; HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, Hong Kong.
  • Eggermont D; VIB-UGent Center for Medical Biotechnology, Ghent, Belgium.
  • Lee HHY; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • Thery F; HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, Hong Kong.
  • Ho J; Department of Pathology, University of Hong Kong, Hong Kong SAR, Hong Kong.
  • van Leur SW; VIB-UGent Center for Medical Biotechnology, Ghent, Belgium.
  • Ng WWS; HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, Hong Kong.
  • Siu LYL; Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, UK.
  • Beling A; HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, Hong Kong.
  • Ploegh H; HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, Hong Kong.
  • Pinto-Fernandez A; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biochemistry, Berlin, Germany.
  • Damianou A; Deutsches Zentrum für Herz-Kreislauf-Forschung, partner site Berlin, Germany.
  • Kessler B; Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
  • Impens F; Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Mok CKP; Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Sanyal S; Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Nat Immunol ; 22(11): 1416-1427, 2021 11.
Article in English | MEDLINE | ID: covidwho-1475314
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ubiquitins / Cytokines / SARS-CoV-2 / COVID-19 / Inflammation / Macrophages Limits: Humans Language: English Journal: Nat Immunol Journal subject: Allergy and Immunology Year: 2021 Document Type: Article Affiliation country: S41590-021-01035-8

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Ubiquitins / Cytokines / SARS-CoV-2 / COVID-19 / Inflammation / Macrophages Limits: Humans Language: English Journal: Nat Immunol Journal subject: Allergy and Immunology Year: 2021 Document Type: Article Affiliation country: S41590-021-01035-8