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

Hazel Stewart, Yongxu Lu, Sarah O'Keefe, Anusha Valpadashi, Luis Cruz-Zaragoza, Hendrik Michel, Samantha Nguyen, George Carnell, Nina Lukhovitskaya, Rachel Milligan, Irwin Jungreis, Valeria Lulla, Andrew Davidson, David Matthews, Stephen High, Peter Rehling, Edward Emmott, Johnathan Heeney, James Edgar, Geoffrey SmithAndrew Firth

Research output: Contribution to journalArticleScientificpeer-review

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 localises to mitochondria during infection, where it inhibits innate immunity by restricting IFN-β production, but not NF-κB activation or JAK-STAT signalling downstream of type I IFN stimulation. We find that ORF3c acts 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 uncharacterised mechanism of innate immune evasion by this important human pathogen.
Original languageEnglish
Article number108080
JournaliScience
Volume26
Issue number11
ISSN2589-0042
DOIs
Publication statusPublished - 17 Nov 2023
Externally publishedYes
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 1182 Biochemistry, cell and molecular biology

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