Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities.
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
SARS-CoV-2
/ immunology
Vero Cells
Viral Nonstructural Proteins
/ immunology
Viral Proteins
/ immunology
COVID-19
SARS-CoV
SARS-CoV-2
autophagy
cytokine
immune evasion
innate immunity
interferon
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
18 05 2021
18 05 2021
Historique:
received:
10
11
2020
revised:
03
03
2021
accepted:
22
04
2021
pubmed:
12
5
2021
medline:
29
5
2021
entrez:
11
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33974846
pii: S2211-1247(21)00465-4
doi: 10.1016/j.celrep.2021.109126
pmc: PMC8078906
pii:
doi:
Substances chimiques
Antiviral Agents
0
Interferon Type I
0
Viral Nonstructural Proteins
0
Viral Proteins
0
Receptor, Interferon alpha-beta
156986-95-7
Interferons
9008-11-1
nsp14 protein, SARS coronavirus
EC 2.1.1.56
Exoribonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109126Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests F.I.S. is a co-founder of DiosCURE Therapeutics SE and a consultant to IFM Therapeutics.
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