Cell Rep
. 2021 Apr 27;109126.
doi: 10.1016/j.celrep.2021.109126. Online ahead of print.
Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities
Manuel Hayn 1 , Maximilian Hirschenberger 1 , Lennart Koepke 1 , Rayhane Nchioua 1 , Jan Hendrik Straub 1 , Susanne Klute 1 , Victoria Hunszinger 1 , Fabian Zech 1 , Caterina Prelli Bozzo 1 , Wasim Aftab 2 , Maria H?nholt Christensen 3 , Carina Conzelmann 1 , Janis Alexander M?ller 1 , Smitha Srinivasachar Badarinarayan 4 , Christina Martina St?rzel 1 , Ignasi Forne 5 , Steffen Stenger 6 , Karl-Klaus Conzelmann 7 , Jan M?nch 1 , Florian Ingo Schmidt 3 , Daniel Sauter 4 , Axel Imhof 5 , Frank Kirchhoff 1 , Konstantin Maria Johannes Sparrer 8
Affiliations
- PMID: 33974846
- PMCID: PMC8078906
- DOI: 10.1016/j.celrep.2021.109126
Abstract
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-? and -?1. 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.
Keywords: COVID-19; SARS-CoV; SARS-CoV-2; autophagy; cytokine; immune evasion; innate immunity; interferon.