SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy

Li, Xingyu; Hou, Peili; Ma, Wenqing; Wang, Xuefeng; Wang, Hongmei; Yu, Zhangping; Chang, Huasong; Wang, Tiecheng; Jin, Sun; Wang, Xue; Wang, Wenqi; Zhao, Yingxin; Zhao, Yong; Xu, Chunqing; Ma, Xiaomei; Gao, Yuwei; He, Hongbin

doi:10.1038/s41423-021-00807-4

Cited by 141 publications

(129 citation statements)

References 58 publications

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“…ORF9b and ORF9c were shown to be able to suppress innate immunity and modulate mitochondria-associated functions and ER stress response, respectively [ 17 , 18 ]. The importance of ORF10 in SARS-CoV-2 infection is controversial as one study reported that ORF10 is dispensable for viral replication, while another study showed that ORF10 can promote viral replication by inhibiting the MAVS-mediated type I IFN signaling pathway [ 19 , 20 ]. It is unclear why these viral proteins can affect multiple distinct signaling pathway reporter promoters.…”

Section: Resultsmentioning

confidence: 99%

Signaling Pathway Reporter Screen with SARS-CoV-2 Proteins Identifies nsp5 as a Repressor of p53 Activity

Kumar

Grams

Bloom

et al. 2022

Viruses

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The dysregulation of host signaling pathways plays a critical role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and viral pathogenesis. While a number of viral proteins that can block type I IFN signaling have been identified, a comprehensive analysis of SARS-CoV-2 proteins in the regulation of other signaling pathways that can be critical for viral infection and its pathophysiology is still lacking. Here, we screened the effect of 21 SARS-CoV-2 proteins on 10 different host signaling pathways, namely, Wnt, p53, TGFβ, c-Myc, Hypoxia, Hippo, AP-1, Notch, Oct4/Sox2, and NF-κB, using a luciferase reporter assay. As a result, we identified several SARS-CoV-2 proteins that could act as activators or inhibitors for distinct signaling pathways in the context of overexpression in HEK293T cells. We also provided evidence for p53 being an intrinsic host restriction factor of SARS-CoV-2. We found that the overexpression of p53 is capable of reducing virus production, while the main viral protease nsp5 can repress the transcriptional activity of p53, which depends on the protease function of nsp5. Taken together, our results provide a foundation for future studies, which can explore how the dysregulation of specific signaling pathways by SARS-CoV-2 proteins can control viral infection and pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Signaling Pathway Reporter Screen with SARS-CoV-2 Proteins Identifies nsp5 as a Repressor of p53 Activity

Kumar

Grams

Bloom

et al. 2022

Viruses

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“…ORF9a, 9b, and 9c are suggested to take part in inhibiting INF signaling and favoring viral replication ( Figure 4 ) [ 189 , 190 , 191 , 192 ]. ORF10 increases MAVS degradation, promoting viral reproduction [ 193 ].…”

Section: Mitochondriamentioning

confidence: 99%

Human Cell Organelles in SARS-CoV-2 Infection: An Up-to-Date Overview

Gorący

Rosik

Szostak

et al. 2022

Viruses

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Since the end of 2019, the whole world has been struggling with the life-threatening pandemic amongst all age groups and geographic areas caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). The Coronavirus Disease 2019 (COVID-19) pandemic, which has led to more than 468 million cases and over 6 million deaths reported worldwide (as of 20 March 2022), is one of the greatest threats to human health in history. Meanwhile, the lack of specific and irresistible treatment modalities provoked concentrated efforts in scientists around the world. Various mechanisms of cell entry and cellular dysfunction were initially proclaimed. Especially, mitochondria and cell membrane are crucial for the course of infection. The SARS-CoV-2 invasion depends on angiotensin converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and cluster of differentiation 147 (CD147), expressed on host cells. Moreover, in this narrative review, we aim to discuss other cell organelles targeted by SARS-CoV-2. Lastly, we briefly summarize the studies on various drugs.

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“…Targeted overexpression studies have also suggested ORF3b and ORF9b to act as IFN antagonists ( Jiang et al, 2020 ; Konno et al, 2020 ; Wu et al, 2021 ). Recently, the controversial ORF10 was shown to suppress type I IFN production when overexpressed in HeLa-ACE2 cells ( Li X. et al, 2021 ). The authors also co-expressed proteins in the RIG-I/MAVS signaling pathway and found that overexpression of ORF10 resulted in a significant decrease in the levels of MAVS, suggesting that it interferes with IFN induction through the MAVS pathway.…”

Section: Identification Of Viral Innate Immune Evasion Mechanisms: a ...mentioning

confidence: 99%

Uncovering Novel Viral Innate Immune Evasion Strategies: What Has SARS-CoV-2 Taught Us?

et al. 2022

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The ongoing SARS-CoV-2 pandemic has tested the capabilities of public health and scientific community. Since the dawn of the twenty-first century, viruses have caused several outbreaks, with coronaviruses being responsible for 2: SARS-CoV in 2007 and MERS-CoV in 2013. As the border between wildlife and the urban population continue to shrink, it is highly likely that zoonotic viruses may emerge more frequently. Furthermore, it has been shown repeatedly that these viruses are able to efficiently evade the innate immune system through various strategies. The strong and abundant antiviral innate immunity evasion strategies shown by SARS-CoV-2 has laid out shortcomings in our approach to quickly identify and modulate these mechanisms. It is thus imperative that there be a systematic framework for the study of the immune evasion strategies of these viruses, to guide development of therapeutics and curtail transmission. In this review, we first provide a brief overview of general viral evasion strategies against the innate immune system. Then, we utilize SARS-CoV-2 as a case study to highlight the methods used to identify the mechanisms of innate immune evasion, and pinpoint the shortcomings in the current paradigm with its focus on overexpression and protein-protein interactions. Finally, we provide a recommendation for future work to unravel viral innate immune evasion strategies and suitable methods to aid in the study of virus-host interactions. The insights provided from this review may then be applied to other viruses with outbreak potential to remain ahead in the arms race against viral diseases.

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SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy

Cited by 141 publications

References 58 publications

Signaling Pathway Reporter Screen with SARS-CoV-2 Proteins Identifies nsp5 as a Repressor of p53 Activity

Signaling Pathway Reporter Screen with SARS-CoV-2 Proteins Identifies nsp5 as a Repressor of p53 Activity

Human Cell Organelles in SARS-CoV-2 Infection: An Up-to-Date Overview

Uncovering Novel Viral Innate Immune Evasion Strategies: What Has SARS-CoV-2 Taught Us?

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