Abstract
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.
Highlights
Our results demonstrated that the HCV phosphoprotein non-structural protein 5A (NS5A) can independently induce alterations in the mitochondrial dynamics that culminate in the induction of mitophagy, as evidenced by Parkin translocation and LC3II
Due to the importance of HCV NS5A in the viral life cycle and its ability to modulate a plethora of cellular activities, we hypothesized that the viral phosphoprotein may play a key role in influencing host cell auto/mitophagy
Since the accumulation of damaged mitochondria is detrimental to cell survival [35], quality control of the injured mitochondria via mitophagy is crucial for the survival of the HCV-infected cells [36]
Summary
Hepatitis C virus infects approximately 3% of the world’s population [1], predisposing the majority to end-stage liver diseases such as liver cirrhosis and hepatocellular carcinoma (HCC) [2]. Unlike non-specific autophagy involving bulk degradation of old or dysfunctional cytoplasmic contents, mitophagy requires additional molecular regulators for the selective degradation of the mitochondria. Key among these regulators include the E3 ubiquitin ligase, Parkin, predominantly localized in the cytoplasm [12], and the PTEN-induced putative kinase 1 (PINK1), a serine-threonine kinase [13]. The expression of HCV core, which has been recently shown to physically interact with Parkin and prevent its translocation to the mitochondria, inhibited mitophagy in both cells harboring the HCV replicating subgenomes and expressing NS5A. Our results identified NS5A as a regulator of HCV-induced mitophagy with implications in advancing our knowledge of HCV-host cell interaction
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