The SARS-CoV-2 protein ORF3c is a mitochondrial modulator of innate immunity.


Stewart, Hazel ORCID: 0000-0003-1438-1089, Lu, Yongxu, O'Keefe, Sarah ORCID: 0000-0002-1744-0198, Valpadashi, Anusha ORCID: 0009-0006-4329-9876, Cruz-Zaragoza, Luis Daniel ORCID: 0000-0001-9568-0245, Michel, Hendrik A ORCID: 0000-0001-7025-5605, Nguyen, Samantha K, Carnell, George W, Lukhovitskaya, Nina, Milligan, Rachel et al (show 12 more authors) (2023) The SARS-CoV-2 protein ORF3c is a mitochondrial modulator of innate immunity. iScience, 26 (11). 108080-. ISSN 2589-0042, 2589-0042

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Abstract

The SARS-CoV-2 genome encodes a multitude of accessory proteins. Using comparative genomic approaches, an additional accessory protein, ORF3c, has been predicted to be encoded within the ORF3a sgmRNA. Expression of ORF3c during infection has been confirmed independently by ribosome profiling. Despite ORF3c also being present in the 2002-2003 SARS-CoV, its function has remained unexplored. Here we show that ORF3c localizes to mitochondria, where it inhibits innate immunity by restricting IFN-β production, but not NF-κB activation or JAK-STAT signaling downstream of type I IFN stimulation. We find that ORF3c is inhibitory after stimulation with cytoplasmic RNA helicases RIG-I or MDA5 or adaptor protein MAVS, but not after TRIF, TBK1 or phospho-IRF3 stimulation. ORF3c co-immunoprecipitates with the antiviral proteins MAVS and PGAM5 and induces MAVS cleavage by caspase-3. Together, these data provide insight into an uncharacterized mechanism of innate immune evasion by this important human pathogen.

Item Type: Article
Uncontrolled Keywords: Immunology, Microbiology, Molecular biology, Proteomics
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 07 May 2025 07:23
Last Modified: 07 May 2025 07:23
DOI: 10.1016/j.isci.2023.108080
Related Websites:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3192644
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