Hepatitis C virus NS5A protein cooperates with phosphatidylinositol 4-kinase IIIα to induce mitochondrial fragmentation

Siu, Gavin Ka Yu; Zhou, Fan; Yu, Man; Zhang, Leiliang; Wang, Tuanlao; Liang, Yongheng; Chen, Yangchao; Chan, Hsiao Chang; Yu, Sidney

doi:10.1038/srep23464

Cited by 14 publications

(17 citation statements)

References 38 publications

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“…NS5A prevented the activation of the caspase-3, presumably through the inhibition of caspase-9. Notably, this is in agreement with the literature data, as this protein was shown earlier to use multiple strategies to block inner pathways of apoptosis by interfering with various host factors [ 8 , 9 , 41 ]. Since the inner pathway of apoptosis is activated through mitochondrial dysfunction, the reason why NS5A did not induce it while the HCV core did does not seem obvious; both of them triggered the massive production of ROS [ 42 , 43 ].…”

Section: Discussionsupporting

confidence: 92%

Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells

Масалова

Леснова

Solyev

et al. 2017

IJMS

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The hepatitis C virus (HCV) causes chronic liver disease leading to fibrosis, cirrhosis, and hepatocellular carcinoma. HCV infection triggers various types of cell death which contribute to hepatitis C pathogenesis. However, much is still unknown about the impact of viral proteins on them. Here we present the results of simultaneous immunocytochemical analysis of markers of apoptosis, autophagy, and necrosis in Huh7.5 cells expressing individual HCV proteins or their combinations, or harboring the virus replicon. Stable replication of the full-length HCV genome or transient expression of its core, Е1/Е2, NS3 and NS5B led to the death of 20–47% cells, 72 h posttransfection, whereas the expression of the NS4A/B, NS5A or NS3-NS5B polyprotein did not affect cell viability. HCV proteins caused different impacts on the activation of caspases-3, -8 and -9 and on DNA fragmentation. The structural core and E1/E2 proteins promoted apoptosis, whereas non-structural NS4A/B, NS5A, NS5B suppressed apoptosis by blocking various members of the caspase cascade. The majority of HCV proteins also enhanced autophagy, while NS5A also induced necrosis. As a result, the death of Huh7.5 cells expressing the HCV core was induced via apoptosis, the cells expressing NS3 and NS5B via autophagy-associated death, and the cells expressing E1/E2 glycoproteins or harboring HCV the replicon via both apoptosis and autophagy.

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Section: Discussionsupporting

confidence: 92%

Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells

Масалова

Леснова

Solyev

et al. 2017

IJMS

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“…In contrast to these findings, two other studies have reported DENV-induced mitochondrial fragmentation that is mediated by mitofusin degradation 152,153 . These studies suggest a mechanism similar to HCV in which virus-induced mitochondrial fission inhibits apoptosis and alleviates immune activation 118,154 . The differences between these reported observations could arise from differences in experimental setup or host cells that were used for infection.…”

Section: Mitochondriamentioning

confidence: 92%

“…In the case of HCV, viral proteins are enriched on mitochondria and MAMs, and viral infection promotes mitochondrial fragmentation and mitophagy 118,154,155 (FIG. 4).…”

Section: Mitochondriamentioning

confidence: 99%

Rewiring cellular networks by members of the Flaviviridae family

et al. 2018

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Members of the Flaviviridae virus family comprise a large group of enveloped viruses with a single-strand RNA genome of positive polarity. Several genera belong to this family, including the Hepacivirus genus, of which hepatitis C virus (HCV) is the prototype member, and the Flavivirus genus, which contains both dengue virus and Zika virus. Viruses of these genera differ in many respects, such as the mode of transmission or the course of infection, which is either predominantly persistent in the case of HCV or acutely self-limiting in the case of flaviviruses. Although the fundamental replication strategy of Flaviviridae members is similar, during the past few years, important differences have been discovered, including the way in which these viruses exploit cellular resources to facilitate viral propagation. These differences might be responsible, at least in part, for the various biological properties of these viruses, thus offering the possibility to learn from comparisons. In this Review, we discuss the current understanding of how Flaviviridae viruses manipulate and usurp cellular pathways in infected cells. Specifically, we focus on comparing strategies employed by flaviviruses with those employed by hepaciviruses, and we discuss the importance of these interactions in the context of viral replication and antiviral therapies.

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“…It has been found to interact with numerous cellular pathways via its conserved polyprotein cluster [8], which matches the Src homology 3 binding motif of many signaling molecules [9]. Interestingly, NS5A has recently been reported to induce mitochondrial fragmentation [10], which is important for the induction of mitophagy.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C Virus Non-Structural Protein 5A (NS5A) Disrupts Mitochondrial Dynamics and Induces Mitophagy

Jassey

Liu

Changou

et al. 2019

Cells

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Mitophagy is a selective form of autophagy, targeting damaged mitochondria for lysosomal degradation. Although HCV infection has been shown to induce mitophagy, the precise underlying mechanism and the effector protein responsible remain unclear. Herein, we demonstrated that the HCV non-structural protein 5A (NS5A) plays a key role in regulating cellular mitophagy. Specifically, the expression of HCV NS5A in the hepatoma cells triggered hallmarks of mitophagy including mitochondrial fragmentation, loss of mitochondrial membrane potential, and Parkin translocation to the mitochondria. Furthermore, mitophagy induction through the expression of NS5A led to an increase in autophagic flux as demonstrated by an accumulation of LC3II in the presence of bafilomycin and a time-dependent decrease in p62 protein level. Intriguingly, the expression of NS5A concomitantly enhanced reactive oxygen species (ROS) production, and treatment with an antioxidant attenuated the NS5A-induced mitophagy event. These phenomena are similarly recapitulated in the NS5A-expressing HCV subgenomic replicon cells. Finally, we demonstrated that expression of HCV core, which has been documented to inhibit mitophagy, blocked the mitophagy induction both in cells harboring HCV replicating subgenomes or expressing NS5A alone. Our results, therefore, identified a new role for NS5A as an important regulator of HCV-induced mitophagy and have implications to broadening our understanding of the HCV-mitophagy interplay.

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Hepatitis C virus NS5A protein cooperates with phosphatidylinositol 4-kinase IIIα to induce mitochondrial fragmentation

Cited by 14 publications

References 38 publications

Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells

Modulation of Cell Death Pathways by Hepatitis C Virus Proteins in Huh7.5 Hepatoma Cells

Rewiring cellular networks by members of the Flaviviridae family

Hepatitis C Virus Non-Structural Protein 5A (NS5A) Disrupts Mitochondrial Dynamics and Induces Mitophagy

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