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Endoplasmic Reticulum Stress Induced Synthesis of a Novel Viral Factor Mediates Efficient Replication of Genotype-1 Hepatitis E Virus.

ABSTRACT: Hepatitis E virus (HEV) causes acute hepatitis in many parts of the world including Asia, Africa and Latin America. Though self-limiting in normal individuals, it results in ~30% mortality in infected pregnant women. It has also been reported to cause acute and chronic hepatitis in organ transplant patients. Of the seven viral genotypes, genotype-1 virus infects humans and is a major public health concern in South Asian countries. Sporadic cases of genotype-3 and 4 infection in human and animals such as pigs, deer, mongeese have been reported primarily from industrialized countries. Genotype-5, 6 and 7 viruses are known to infect animals such as wild boar and camel, respectively. Genotype-3 and 4 viruses have been successfully propagated in the laboratory in mammalian cell culture. However, genotype-1 virus replicates poorly in mammalian cell culture and no other efficient model exists to study its life cycle. Here, we report that endoplasmic reticulum (ER) stress promotes genotype-1 HEV replication by inducing cap-independent, internal initiation mediated translation of a novel viral protein (named ORF4). Importantly, ORF4 expression and stimulatory effect of ER stress inducers on viral replication is specific to genotype-1. ORF4 protein sequence is mostly conserved among genotype-1 HEV isolates and ORF4 specific antibodies were detected in genotype-1 HEV patient serum. ORF4 interacted with multiple viral and host proteins and assembled a protein complex consisting of viral helicase, RNA dependent RNA polymerase (RdRp), X, host eEF1?1 (eukaryotic elongation factor 1 isoform-1) and tubulin?. In association with eEF1?1, ORF4 stimulated viral RdRp activity. Furthermore, human hepatoma cells that stably express ORF4 or engineered proteasome resistant ORF4 mutant genome permitted enhanced viral replication. These findings reveal a positive role of ER stress in promoting genotype-1 HEV replication and pave the way towards development of an efficient model of the virus.

SUBMITTER: Nair VP

PROVIDER: S-EPMC4817972 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Endoplasmic Reticulum Stress Induced Synthesis of a Novel Viral Factor Mediates Efficient Replication of Genotype-1 Hepatitis E Virus.

Nair Vidya P VP Anang Saumya S Subramani Chandru C Madhvi Abhilasha A Bakshi Karishma K Srivastava Akriti A Shalimar Nayak Baibaswata B Ranjith Kumar C T CT Surjit Milan M

PLoS pathogens 20160401 4

Hepatitis E virus (HEV) causes acute hepatitis in many parts of the world including Asia, Africa and Latin America. Though self-limiting in normal individuals, it results in ~30% mortality in infected pregnant women. It has also been reported to cause acute and chronic hepatitis in organ transplant patients. Of the seven viral genotypes, genotype-1 virus infects humans and is a major public health concern in South Asian countries. Sporadic cases of genotype-3 and 4 infection in human and animals ...[more]

PMID: 27035822

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Project description:Hepatitis C virus (HCV) causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). Wild-type peroxisome proliferator-activated receptor gamma coactivator 1 alpha (WT-PGC-1?) is essential in hepatic gluconeogenesis and has recently been demonstrated to link HCV infection to hepatic insulin resistance (IR). A recent study has characterized a novel human liver-specific PGC-1? (L-PGC-1?) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1? expression and the mechanism by which HCV modulates WT-PGC-1?/L-PGC-1? remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1? and L-PGC-1?, which further promoted HCV production. The upregulation of both PGC-1? isoforms depended on HCV RNA replication. By using promoter-luciferase reporters, kinase inhibitors, and dominant negative mutants, we further observed that the HCV-induced upregulation of WT-PGC-1? was mediated by the phosphorylation of cyclic AMP (cAMP)-responsive element-binding protein (CREB), whereas that of L-PGC-1? was mediated by CREB phosphorylation and forkhead box O1 dephosphorylation. Moreover, HCV infection induced endoplasmic reticulum (ER) stress, and pharmacological induction of ER stress upregulated WT-PGC-1?/L-PGC-1? and phosphorylated CREB. In contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1?/L-PGC-1? upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1? with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1? and L-PGC-1? through an ER stress-mediated, phosphorylated CREB-dependent pathway, and both PGC-1? isoforms promote HCV production in turn.HCV causes not only severe liver problems but also extrahepatic manifestations, such as insulin resistance (IR). As a key regulator in energy metabolism, wild-type PGC-1? (WT-PGC-1?), has recently been demonstrated to link HCV infection to hepatic IR. A recent study has characterized a novel human liver-specific PGC-1? (L-PGC-1?), which reflects human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1? expression and the mechanism by which HCV regulates WT-PGC-1?/L-PGC-1? remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1? and L-PGC-1?, which further promoted HCV production. WT-PGC-1? upregulation was mediated by CREB phosphorylation, whereas L-PGC-1? upregulation was mediated by CREB phosphorylation and FoxO1 dephosphorylation. HCV-induced ER stress mediated WT-PGC-1?/L-PGC-1? upregulation and CREB phosphorylation. Overall, this study provides new insights into the mechanism by which HCV upregulates WT-PGC-1?/L-PGC-1? and highlights the novel intervention of HCV-ER stress-PGC-1? signaling for HCV therapy and HCV-induced IR therapy.

Dataset Information

Endoplasmic Reticulum Stress Induced Synthesis of a Novel Viral Factor Mediates Efficient Replication of Genotype-1 Hepatitis E Virus.

Publications

Endoplasmic Reticulum Stress Induced Synthesis of a Novel Viral Factor Mediates Efficient Replication of Genotype-1 Hepatitis E Virus.

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