Details

Autor(en) / Beteiligte

• Stewart, Hazel
• Lu, Yongxu
• O’Keefe, Sarah
• Valpadashi, Anusha
• Cruz-Zaragoza, Luis Daniel
• Michel, Hendrik A.
• Nguyen, Samantha K.
• Carnell, George W.
• Lukhovitskaya, Nina
• Milligan, Rachel
• Adewusi, Yasmin
• Jungreis, Irwin
• Lulla, Valeria
• Matthews, David A.
• High, Stephen
• Rehling, Peter
• Emmott, Edward
• Heeney, Jonathan L.
• Davidson, Andrew D.
• Edgar, James R.
• Smith, Geoffrey L.
• Firth, Andrew E.

Titel

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

Ist Teil von

• iScience, 2023-11, Vol.26 (11), p.108080-108080, Article 108080

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •The accessory protein ORF3c is encoded by a “hidden” ORF, which overlaps ORF3a•ORF3c is expressed by leaky scanning, at approximately the same levels as ORF3a•ORF3c localizes to mitochondria and interacts with both MAVS and PGAM5•ORF3c expression leads to a reduction in IFNB transcripts and IFN-β protein levels Molecular biology; Immunology; Microbiology; Proteomics