Abstract
Autophagy is a host mechanism for cellular homeostatic control. Intracellular stresses are symptoms of, and responses to, dysregulation of the physiological environment of the cell. Alternative gene transcription splicing is a mechanism potentially used by a host to respond to physiological or pathological challenges. Here, we aimed to confirm opposite effects of two isoforms of the human autophagy-related protein ATG10 on an HCV subgenomic replicon in zebrafish. A liver-specific HCV subreplicon model was established and exhibited several changes in gene expression typically induced by HCV infection, including overexpression of several HCV-dependent genes (argsyn, leugpcr, rasgbd, and scaf-2), as well as overexpression of several ER stress related genes (atf4, chop, atf6, and bip). Autophagy flux was blocked in the HCV model. Our results indicated that the replication of the HCV subreplicon was suppressed via a decrease in autophagosome formation caused by the autophagy inhibitor 3MA, but enhanced via dysfunction in the lysosomal degradation caused by another autophagy inhibitor CQ. Human ATG10, a canonical isoform in autophagy, facilitated the amplification of the HCV-subgenomic replicon via promoting autophagosome formation. ATG10S, a non-canonical short isoform of the ATG10 protein, promoted autophagy flux, leading to lysosomal degradation of the HCV-subgenomic replicon. Human ATG10S may therefore inhibit HCV replication, and may be an appropriate target for future antiviral drug screening.
Highlights
Worldwide, ∼150 million people are chronically infected with hepatitis C virus (HCV), a virus that leads to the development of serious liver diseases such as liver cirrhosis, liver fibrosis, and hepatocellular carcinoma (Lavanchy, 2011; Chung and Baumert, 2014)
endoplasmic reticular (ER) stress and Unfolded protein response (UPR) play an important role in the HCV lifecycle in which autophagy is involved
The coordinated expression of the UPR mediators, ATF4 and CHOP triggers the transcription of numerous UPR target genes including autophagy-regulating genes ATG5 and LC3B (Rouschop et al, 2010; B’Chir et al, 2014)
Summary
Worldwide, ∼150 million people are chronically infected with hepatitis C virus (HCV), a virus that leads to the development of serious liver diseases such as liver cirrhosis, liver fibrosis, and hepatocellular carcinoma (Lavanchy, 2011; Chung and Baumert, 2014). In a HCV subreplicon cell model, we showed that human ATG10 (the long atg transcript) mediates Atg12-Atg conjugation in the early autophagosome formation and promoted replication of the HCV; while hATG10S (the short ATG10 transcript) significantly suppressed replication of the HCV subreplicon in HepG2 cells (a hepatocellular carcinoma cell line) (Zhao et al, 2017). These finding provided new insights into host defense mechanisms and compromise during viral invasion, further in vivo supporting data was required
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