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SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells

By Ana Dominguez Andres, Yongmei Feng, Alexandre Rosa Campos, Jun Yin, Chih-Cheng Yang, Brian James, Rabi Murad, Hyungsoo Kim, Aniruddha J Deshpande, David E Gordon, Nevan J Krogan, Raffaella Pippa, Ze'ev A Ronai

Posted 19 Aug 2020
bioRxiv DOI: 10.1101/2020.08.18.256776

Disrupted antiviral immune responses are associated with severe COVID-19, the disease caused by SAR-CoV-2. Here, we show that the 73-amino-acid protein encoded by ORF9c of the viral genome contains a putative transmembrane domain, interacts with membrane proteins in multiple cellular compartments, and impairs antiviral processes in a lung epithelial cell line. Proteomic, interactome, and transcriptomic analyses, combined with bioinformatic analysis, revealed that expression of only this highly unstable small viral protein impaired interferon signaling, antigen presentation, and complement signaling, while inducing IL-6 signaling. Furthermore, we showed that interfering with ORF9c degradation by either proteasome inhibition or inhibition of the ATPase VCP blunted the effects of ORF9c. Our study indicated that ORF9c enables immune evasion and coordinates cellular changes essential for the SARS-CoV-2 life cycle. ### Competing Interest Statement ZAR is a co-founder and serves as scientific advisor to Pangea Therapeutics. All other authors declare no competing interests.

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