SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria

Zong, Shan; Wu, Yan; Li, Weiling; Qin, You; Peng, Qian; Wang, Chenghai; Wan, Pin; Bai, Tao; Ma, Yanling; Sun, Binlian; Qiao, Jialu

doi:10.1016/j.virs.2023.05.003

Cited by 15 publications

(3 citation statements)

References 42 publications

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“…Oxidative stress, characterized by an imbalance between ROS production and the cellular antioxidant defense system, often serves as a catalyst for mitochondrial structure and function damage ( Zorov et al, 2014 ; van Hameren et al, 2019 ). Mitochondrial damage, in turn, becomes a pivotal trigger for the activation of autophagy, a cellular mechanism designed to maintain balance and eliminate compromised cellular components ( Zong et al, 2023 ). Moreover, oxidative regulations impact all stages of autophagy, encompassing induction, phagophore nucleation, phagophore expansion, autophagosome maturation, cargo delivery to the lysosome, and, ultimately, the degradation of cargo and recycling of products, alongside the transcription of autophagy genes ( Zhou et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Involvement of autophagy in mesaconitine-induced neurotoxicity in HT22 cells revealed through integrated transcriptomic, proteomic, and m6A epitranscriptomic profiling

Lin,

Zhang,

et al. 2024

Front. Pharmacol.

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Background: Mesaconitine (MA), a diester-diterpenoid alkaloid extracted from the medicinal herb Aconitum carmichaelii, is commonly used to treat various diseases. Previous studies have indicated the potent toxicity of aconitum despite its pharmacological activities, with limited understanding of its effects on the nervous system and the underlying mechanisms.Methods: HT22 cells and zebrafish were used to investigate the neurotoxic effects of MA both in vitro and in vivo, employing multi-omics techniques to explore the potential mechanisms of toxicity.Results: Our results demonstrated that treatment with MA induces neurotoxicity in zebrafish and HT22 cells. Subsequent analysis revealed that MA induced oxidative stress, as well as structural and functional damage to mitochondria in HT22 cells, accompanied by an upregulation of mRNA and protein expression related to autophagic and lysosomal pathways. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed a correlation between the expression of autophagy-related genes and N6-methyladenosine (m6A) modification following MA treatment. In addition, we identified METTL14 as a potential regulator of m6A methylation in HT22 cells after exposure to MA.Conclusion: Our study has contributed to a thorough mechanistic elucidation of the neurotoxic effects caused by MA, and has provided valuable insights for optimizing the rational utilization of traditional Chinese medicine formulations containing aconitum in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Involvement of autophagy in mesaconitine-induced neurotoxicity in HT22 cells revealed through integrated transcriptomic, proteomic, and m6A epitranscriptomic profiling

Lin,

Zhang,

et al. 2024

Front. Pharmacol.

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“…It can inhibit the production of type I and type III interferons (IFNs) by targeting key signaling molecules such as RIG-I/MDA5, TRIF, and STING ( 9 ). Furthermore, NSP8 can damage the mitochondria and induce incomplete mitophagy ( 10 ). These findings highlight the multifunctionality of NSP8 and its potential role in modulating host immune response and cellular processes during SARS-CoV-2 replication.…”

Section: Introductionmentioning

confidence: 99%

The E3 ligase TRIM22 restricts SARS-CoV-2 replication by promoting proteasomal degradation of NSP8

Fan,

Zhou,

Wei

et al. 2024

mBio

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Replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is mediated by a complex of non-structural proteins (NSPs), of which NSP7 and NSP8 serve as subunits and play a key role in promoting the activity of RNA-dependent RNA polymerase (RdRp) of NSP12. However, the stability of subunits of the RdRp complex has rarely been reported. Here, we found that NSP8 was degraded by the proteasome in host cells, and identified tripartite motif containing 22 (TRIM22) as its E3 ligase. The interferon (IFN) signaling pathway was activated upon viral invasion into host cells, and TRIM22 expression increased. TRIM22 interacted with NSP8 and ubiquitinated it at Lys97 via K48-type ubiquitination. TRIM22 overexpression significantly reduced viral RNA and protein levels. Knockdown of TRIM22 enhanced viral replication. This study provides a new explanation for treating patients suffering from SARS-CoV-2 with IFNs and new possibilities for drug development targeting the interaction between NSP8 and TRIM22. IMPORTANCE Non-structural proteins (NSPs) play a crucial role in the replication of severe acute respiratory syndrome coronavirus 2, facilitating virus amplification and propagation. In this study, we conducted a comprehensive investigation into the stability of all subunits comprising the RNA-dependent RNA polymerase complex. Notably, our results reveal for the first time that NSP8 is a relatively unstable protein, which is found to be readily recognized and degraded by the proteasome. This degradation process is mediated by the host E3 ligase tripartite motif containing 22 (TRIM22), which is also a member of the interferon stimulated gene (ISG) family. Our study elucidates a novel mechanism of antiviral effect of TRIM22, which utilizes its own E3 ubiquitin ligase activity to hinder viral replication by inducing ubiquitination and subsequent degradation of NSP8. These findings provide new ideas for the development of novel therapeutic strategies. In addition, the conserved property of NSP8 raises the possibility of developing broad antiviral drugs targeting the TRIM22-NSP8 interaction.

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“…Oxidative stress, characterized by an imbalance between ROS production and the cellular antioxidant defense system, often serves as a catalyst for mitochondrial structure and function damage (Zorov et al, 2014;van Hameren et al, 2019). Mitochondrial damage, in turn, becomes a pivotal trigger for the activation of autophagy, a cellular mechanism designed to maintain balance and eliminate compromised cellular components (Zong et al, 2023). Moreover, oxidative regulations impact all stages of autophagy, encompassing induction, phagophore nucleation, phagophore expansion, autophagosome maturation, cargo delivery to the lysosome, and, ultimately, the degradation of cargo and recycling of products, alongside the transcription of autophagy genes (Zhou et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria

Cited by 15 publications

References 42 publications

Involvement of autophagy in mesaconitine-induced neurotoxicity in HT22 cells revealed through integrated transcriptomic, proteomic, and m6A epitranscriptomic profiling

Involvement of autophagy in mesaconitine-induced neurotoxicity in HT22 cells revealed through integrated transcriptomic, proteomic, and m6A epitranscriptomic profiling

The E3 ligase TRIM22 restricts SARS-CoV-2 replication by promoting proteasomal degradation of NSP8

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