Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response

Abstract

1054-1061.)A utophagy is important for removing long-lived proteins and damaged organelles in cells. During autophagy, double-membrane vesicles form to sequester part of the cytoplasm. These double-membrane vesicles, also known as autophagosomes, subsequently fuse with lysosomes to form autolysosomes for the degradation of their contents for recycling. 1 Many genes that are important for autophagy have been identified. Among them is microtubule-associated protein light chain 3 (LC3), whose covalent linkage to phosphatidylethanolamine by the ubiquitin-activating enzyme E1-like protein Atg7 is necessary for the formation of autophagosomes. 2 Hepatitis C virus (HCV) is a positive-stranded RNA virus with a genome size of 9.6 Kb. Infection by this virus can lead to liver cirrhosis and hepatocellular carcinoma. Based on their genetic relatedness, different HCV isolates have been grouped into six major genotypes and many more subtypes. The HCV genome codes for a polyprotein, which is proteolytically cleaved to generate the mature protein products. 3 Recently, a cell culture system for efficient HCV propagation using the JFH1 strain, which belongs to HCV genotype 2a, has been developed. [4][5][6][7] In this system, the HCV JFH1 RNA or its derivative was transfected into human hepatoma cells to direct the replication and release of infectious HCV particles, which could then initiate the next round of infection. In this report, we use this HCV RNA transfection/ infection system to study HCV-host interactions. Our results indicate that HCV induces the accumulation of autophagosomes by activating unfolded protein response (UPR). However, HCV does not enhance autophagic protein degradation. Importantly, this induction of autophagosomes enhanced HCV replication. The persistent induction of the UPR and the Abbreviations: BAF, bafilomycin A1; DMEM, Dulbecco's modified Eagle's medium; DTT, dithiothreitol; ER, endoplasmic reticulum; GFP, green fluorescence protein; HCV, hepatitis C virus; LC3, mRNA, messenger RNA; PERK, siRNA, small interfering RNA; Tg, thapsigargin; UPR, unfolded protein response. From the

Changes in Autophagic Response in Patients with Chronic Hepatitis C Virus Infection

“…4 Several recent in vitro studies have suggested that the autophagic pathway is involved in HCV replication in cultured cells. [5][6][7][8][9][10][11] However, the relevance of such findings in vivo remains unknown because autophagy has never been assessed in chronic hepatitis C (CHC) patients. 2,4 The aims of the present study were to evaluate the autophagic response in CHC patients, and to identify factors influencing the autophagy level in such patients.…”

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

“…67 Studies have shown that there is an accumulation of autophagic vacuoles in HCV-infected hepatocytes; however this autophagy is inefficient as the autophagosomes are not able to increase autophagic protein degradation. The strategies used by HCV to evade and take advantage of autophagy for its replication are: (i) HCV avoids recognition by the autophagic process with rare or no co-localization of HCV proteins in autophagic vacuoles [68][69][70] ;…”

“…(ii) HCV prevents maturation of autophagosomes into autolysosomes 68,69 ; and (iii) HCV utilizes components of autophagy to enhance intracellular replication. The autophagy proteins are likely to be proviral factors for the initial steps of HCV replication.…”

“…The autophagy proteins are likely to be proviral factors for the initial steps of HCV replication. [67][68][69] The autophagy machinery is also subverted in HBV. The autophagosomes are also induced in HBV; but, unlike HCV, the late autophagic vacuoles are detectable in hepatocytes.…”

MHC presentation via autophagy and how viruses escape from it

“…In addition, inhibition of autophagosome degradation might enhance virus particle exocytosis 58 . Furthermore, the stabilization of autophagosome membranes for viral replication has been proposed for other RNA viruses, like the flaviviruses hepatitic C virus (HCV) and dengue virus [59][60][61][62][63] . Moreover, even RNA viruses that do not use autophagosomal membranes for their replication, seem to benefit from inhibition of autophagosome degradation for their release of infectious viruses from infected cells 64 .…”