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Hayn, Manuel; Hirschenberger, Maximilian; Koepke, Lennart; Nchioua, Rayhane; Straub, Jan Hendrik; Klute, Susanne; Hunszinger, Victoria; Zech, Fabian; Bozzo, Caterina Prelli; Aftab, Wasim; Christensen, Maria Honholt; Conzelmann, Carina; Mueller, Janis Alexander; Badarinarayan, Smitha Srinivasachar; Stuerzel, Christina Martina; Forne, Ignasi; Stenger, Steffen; Conzelmann, Karl-Klaus; Muench, Jan; Schmidt, Florian Ingo; Sauter, Daniel; Imhof, Axel; Kirchhoff, Frank and Sparrer, Konstantin Maria Johannes (2021): Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities. In: Cell Reports, Vol. 35, No. 7, 109126

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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-gamma and -lambda 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.

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