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

Accepted version
Peer-reviewed

Type

Article

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Authors

Stewart, Hazel 
Lu, Yongxu 
O'Keefe, Sarah 
Valpadashi, Anusha 
Cruz-Zaragoza, Luis Daniel 

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.

Description

Keywords

Immunology, Microbiology, Molecular biology, Proteomics

Journal Title

iScience

Conference Name

Journal ISSN

2589-0042
2589-0042

Volume Title

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (106207/Z/14/Z)
Wellcome Trust (220814/Z/20/Z)
European Research Council (646891)
Wellcome Trust (090315/Z/09/Z)
Wellcome Trust (216370/Z/19/Z)
MRC (via Imperial College London) (MR/W005611/1)
Wellcome Trust (220620/Z/20/Z)
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