tetano
Editor, Senior Moderator
Cell Mol Immunol
. 2021 Nov 29.
doi: 10.1038/s41423-021-00807-4. Online ahead of print.
SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy
Xingyu Li[SUP] #[/SUP][SUP] 1 [/SUP], Peili Hou[SUP] #[/SUP][SUP] 1 [/SUP], Wenqing Ma[SUP] #[/SUP][SUP] 1 [/SUP], Xuefeng Wang[SUP] #[/SUP][SUP] 2 [/SUP], Hongmei Wang[SUP] 3 [/SUP], Zhangping Yu[SUP] 1 [/SUP], Huasong Chang[SUP] 1 [/SUP], Tiecheng Wang[SUP] 2 [/SUP], Song Jin[SUP] 1 [/SUP], Xue Wang[SUP] 1 [/SUP], Wenqi Wang[SUP] 1 2 [/SUP], Yudong Zhao[SUP] 2 [/SUP], Yong Zhao[SUP] 2 [/SUP], Chunqing Xu[SUP] 1 [/SUP], Xiaomei Ma[SUP] 1 [/SUP], Yuwei Gao[SUP] 4 [/SUP], Hongbin He[SUP] 5 [/SUP]
Affiliations
Abstract
The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused severe morbidity and mortality in humans. It is urgent to understand the function of viral genes. However, the function of open reading frame 10 (ORF10), which is uniquely expressed by SARS-CoV-2, remains unclear. In this study, we showed that overexpression of ORF10 markedly suppressed the expression of type I interferon (IFN-I) genes and IFN-stimulated genes. Then, mitochondrial antiviral signaling protein (MAVS) was identified as the target via which ORF10 suppresses the IFN-I signaling pathway, and MAVS was found to be degraded through the ORF10-induced autophagy pathway. Furthermore, overexpression of ORF10 promoted the accumulation of LC3 in mitochondria and induced mitophagy. Mechanistically, ORF10 was translocated to mitochondria by interacting with the mitophagy receptor Nip3-like protein X (NIX) and induced mitophagy through its interaction with both NIX and LC3B. Moreover, knockdown of NIX expression blocked mitophagy activation, MAVS degradation, and IFN-I signaling pathway inhibition by ORF10. Consistent with our observations, in the context of SARS-CoV-2 infection, ORF10 inhibited MAVS expression and facilitated viral replication. In brief, our results reveal a novel mechanism by which SARS-CoV-2 inhibits the innate immune response; that is, ORF10 induces mitophagy-mediated MAVS degradation by binding to NIX.
Keywords: MAVS; NIX; ORF10; SARS-CoV-2; mitophagy.
. 2021 Nov 29.
doi: 10.1038/s41423-021-00807-4. Online ahead of print.
SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy
Xingyu Li[SUP] #[/SUP][SUP] 1 [/SUP], Peili Hou[SUP] #[/SUP][SUP] 1 [/SUP], Wenqing Ma[SUP] #[/SUP][SUP] 1 [/SUP], Xuefeng Wang[SUP] #[/SUP][SUP] 2 [/SUP], Hongmei Wang[SUP] 3 [/SUP], Zhangping Yu[SUP] 1 [/SUP], Huasong Chang[SUP] 1 [/SUP], Tiecheng Wang[SUP] 2 [/SUP], Song Jin[SUP] 1 [/SUP], Xue Wang[SUP] 1 [/SUP], Wenqi Wang[SUP] 1 2 [/SUP], Yudong Zhao[SUP] 2 [/SUP], Yong Zhao[SUP] 2 [/SUP], Chunqing Xu[SUP] 1 [/SUP], Xiaomei Ma[SUP] 1 [/SUP], Yuwei Gao[SUP] 4 [/SUP], Hongbin He[SUP] 5 [/SUP]
Affiliations
- PMID: 34845370
- DOI: 10.1038/s41423-021-00807-4
Abstract
The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused severe morbidity and mortality in humans. It is urgent to understand the function of viral genes. However, the function of open reading frame 10 (ORF10), which is uniquely expressed by SARS-CoV-2, remains unclear. In this study, we showed that overexpression of ORF10 markedly suppressed the expression of type I interferon (IFN-I) genes and IFN-stimulated genes. Then, mitochondrial antiviral signaling protein (MAVS) was identified as the target via which ORF10 suppresses the IFN-I signaling pathway, and MAVS was found to be degraded through the ORF10-induced autophagy pathway. Furthermore, overexpression of ORF10 promoted the accumulation of LC3 in mitochondria and induced mitophagy. Mechanistically, ORF10 was translocated to mitochondria by interacting with the mitophagy receptor Nip3-like protein X (NIX) and induced mitophagy through its interaction with both NIX and LC3B. Moreover, knockdown of NIX expression blocked mitophagy activation, MAVS degradation, and IFN-I signaling pathway inhibition by ORF10. Consistent with our observations, in the context of SARS-CoV-2 infection, ORF10 inhibited MAVS expression and facilitated viral replication. In brief, our results reveal a novel mechanism by which SARS-CoV-2 inhibits the innate immune response; that is, ORF10 induces mitophagy-mediated MAVS degradation by binding to NIX.
Keywords: MAVS; NIX; ORF10; SARS-CoV-2; mitophagy.