Dataset Information

SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria.

ABSTRACT: Autophagy plays an important role in the interaction between viruses and host cells. SARS-CoV-2 infection can disrupt the autophagy process in target cells. However, the precise molecular mechanism is still unknown. In this study, we discovered that the Nsp8 of SARS-CoV-2 could cause an increasing accumulation of autophagosomes by preventing the fusion of autophagosomes and lysosomes. From further investigation, we found that Nsp8 was present on mitochondria and can damage mitochondria to initiate mitophagy. The results of experiments with immunofluorescence revealed that Nsp8 induced incomplete mitophagy. Moreover, both domains of Nsp8 orchestrated their function during Nsp8-induced mitophagy, in which the N-terminal domain colocalized with mitochondria and the C-terminal domain induced auto/mitophagy. This novel finding expands our understanding of the function of Nsp8 in promoting mitochondrial damage and inducing incomplete mitophagy, which helps us to understand the etiology of COVID-19 as well as open up new pathways for creating SARS-CoV-2 treatment methods.

SUBMITTER: Zong S

PROVIDER: S-EPMC10163945 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria.

Zong Shan S Wu Yan Y Li Weiling W You Qiang Q Peng Qian Q Wang Chenghai C Wan Pin P Bai Tao T Ma Yanling Y Sun Binlian B Qiao Jialu J

Virologica Sinica 20230506 4

Autophagy plays an important role in the interaction between viruses and host cells. SARS-CoV-2 infection can disrupt the autophagy process in target cells. However, the precise molecular mechanism is still unknown. In this study, we discovered that the Nsp8 of SARS-CoV-2 could cause an increasing accumulation of autophagosomes by preventing the fusion of autophagosomes and lysosomes. From further investigation, we found that Nsp8 was present on mitochondria and can damage mitochondria to initia ...[more]

PMID: 37156297

Similar Datasets

Project description:BackgroundNeurological complications are a significant concern of Coronavirus Disease 2019 (COVID-19). However, the pathogenic mechanism of neurological symptoms associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is poorly understood.MethodsWe used Drosophila as a model to systematically analyze SARS-CoV-2 genes encoding structural and accessory proteins and identified the membrane protein (M) that disrupted mitochondrial functions in vivo. The M protein was stereotaxically injected to further assess its effects in the brains of wild-type (WT) and 5 × FAD mice. Omics technologies, including RNA sequencing and interactome analysis, were performed to explore the mechanisms of the effects of M protein both in vitro and in vivo.ResultsSystematic analysis of SARS-CoV-2 structural and accessory proteins in Drosophila identified that the M protein induces mitochondrial fragmentation and dysfunction, leading to reduced ATP production, ROS overproduction, and eventually cell death in the indirect flight muscles. In WT mice, M caused hippocampal atrophy, neural apoptosis, glial activation, and mitochondrial damage. These changes were further aggravated in 5 × FAD mice. M was localized to the Golgi apparatus and genetically interacted with four wheel drive (FWD, a Drosophila homolog of mammalian PI4KIIIβ) to regulate Golgi functions in flies. Fwd RNAi, but not PI4KIIIα RNAi, reversed the M-induced Golgi abnormality, mitochondrial fragmentation, and ATP reduction. Inhibition of PI4KIIIβ activity suppressed the M-induced neuronal cell death. Therefore, M induced mitochondrial fragmentation and apoptosis likely through disruption of Golgi-derived PI(4)P-containing vesicles.ConclusionsM disturbs the distribution and function of Golgi, leading to mitochondrial abnormality and eventually neurodegeneration via a PI4KIIIβ-mediated mechanism. This study reveals a potential mechanism for COVID-19 neurological symptoms and opens a new avenue for development of therapeutic strategies targeting SARS-CoV-2 M or mitochondria.

Project description: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.IMPORTANCENon-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.

Dataset Information

SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria.

Publications

SARS-CoV-2 Nsp8 induces mitophagy by damaging mitochondria.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets