Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities.

Tytuł:: Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities.
Autorzy:: Hayn M; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Hirschenberger M; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Koepke L; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Nchioua R; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Straub JH; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Klute S; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Hunszinger V; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Zech F; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Prelli Bozzo C; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Aftab W; Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Graduate School for Quantitative Biosciences (QBM), Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
Christensen MH; Institute of Innate Immunity, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
Conzelmann C; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Müller JA; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Srinivasachar Badarinarayan S; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany; Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, 72076 Tübingen, Germany.
Stürzel CM; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Forne I; Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
Stenger S; Institute for Medical Microbiology and Hygiene, Ulm University Medical Center, 89081 Ulm, Germany.
Conzelmann KK; Max von Pettenkofer-Institute of Virology, Medical Faculty, and Gene Center, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
Münch J; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Schmidt FI; Institute of Innate Immunity, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
Sauter D; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany; Institute of Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, 72076 Tübingen, Germany.
Imhof A; Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
Kirchhoff F; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Sparrer KMJ; Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany. Electronic address: .
Źródło:: Cell reports [Cell Rep] 2021 May 18; Vol. 35 (7), pp. 109126. Date of Electronic Publication: 2021 Apr 27.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [Cambridge, MA] : Cell Press, c 2012-
MeSH Terms:: COVID-19/*virology
SARS-CoV-2/*immunology
Viral Proteins/*immunology
Animals ; Antiviral Agents/pharmacology ; Autophagosomes/immunology ; Autophagy/immunology ; COVID-19/immunology ; Cell Line ; Chlorocebus aethiops ; Exoribonucleases/immunology ; HEK293 Cells ; HeLa Cells ; Humans ; Immune Evasion ; Immunity, Innate ; Interferon Type I/metabolism ; Interferons/metabolism ; Receptor, Interferon alpha-beta/antagonists & inhibitors ; Receptor, Interferon alpha-beta/immunology ; SARS-CoV-2/pathogenicity ; Vero Cells ; Viral Nonstructural Proteins/immunology
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Contributed Indexing:: Keywords: COVID-19; SARS-CoV; SARS-CoV-2; autophagy; cytokine; immune evasion; innate immunity; interferon
Substance Nomenclature:: 0 (Antiviral Agents)
0 (Interferon Type I)
0 (Viral Nonstructural Proteins)
0 (Viral Proteins)
156986-95-7 (Receptor, Interferon alpha-beta)
9008-11-1 (Interferons)
EC 2.1.1.56 (nsp14 protein, SARS coronavirus)
EC 3.1.- (Exoribonucleases)
Entry Date(s):: Date Created: 20210511 Date Completed: 20210528 Latest Revision: 20231111
Update Code:: 20240105
PubMed Central ID:: PMC8078906
DOI:: 10.1016/j.celrep.2021.109126
PMID:: 33974846
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades most innate immune responses but may still be vulnerable to some. Here, we systematically analyze the impact of SARS-CoV-2 proteins on interferon (IFN) responses and autophagy. We show that SARS-CoV-2 proteins synergize to counteract anti-viral immune responses. For example, Nsp14 targets the type I IFN receptor for lysosomal degradation, ORF3a prevents fusion of autophagosomes and lysosomes, and ORF7a interferes with autophagosome acidification. Most activities are evolutionarily conserved. However, SARS-CoV-2 Nsp15 antagonizes IFN signaling less efficiently than the orthologs of closely related RaTG13-CoV and SARS-CoV-1. Overall, SARS-CoV-2 proteins counteract autophagy and type I IFN more efficiently than type II or III IFN signaling, and infection experiments confirm potent inhibition by IFN-γ and -λ1. Our results define the repertoire and selected mechanisms of SARS-CoV-2 innate immune antagonists but also reveal vulnerability to type II and III IFN that may help to develop safe and effective anti-viral approaches.
Competing Interests: Declaration of interests F.I.S. is a co-founder of DiosCURE Therapeutics SE and a consultant to IFM Therapeutics.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Comment in: Autophagy. 2021 Sep;17(9):2659-2661. (PMID: 34281462)

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