Home » Key Scientific Articles » Endoplasmic reticulum stress links hepatitis C virus RNA replication to wild-type PGC-1{Alpha}/liver-specific PGC-1{Alpha} upregulation.

Endoplasmic reticulum stress links hepatitis C virus RNA replication to wild-type PGC-1{Alpha}/liver-specific PGC-1{Alpha} upregulation.

Yao W1, Cai H1, Li X2, Li T3, Hu L3, Peng T4.

J Virol. 2014 ;88(15):8361-74.

1Laboratory of Viral Immunology, State key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China Sino-French Hoffmann Institute of Immunology, Guangzhou Medical University, Guangzhou, China.and

2Sino-French Hoffmann Institute of Immunology, Guangzhou Medical University, Guangzhou, China.and

3Laboratory of Viral Immunology, State key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.and

4Laboratory of Viral Immunology, State key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China Sino-French Hoffmann Institute of Immunology, Guangzhou Medical University, Guangzhou, China [email protected]

 

Abstract

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{Alpha}) 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{Alpha} (L-PGC-1{Alpha}) transcript, which is proposed to reflect human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1{Alpha} expression and the mechanism by which HCV modulates WT-PGC-1{Alpha}/L-PGC-1{Alpha} remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1{Alpha} and L-PGC-1{Alpha}, which further promoted HCV production. The upregulation of both PGC-1{Alpha} 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{Alpha} was mediated by the phosphorylation of cyclic AMP (cAMP)-responsive element-binding protein (CREB), whereas that of L-PGC-1{Alpha} 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{Alpha}/L-PGC-1{Alpha} and phosphorylated CREB. In contrast, pharmacological inhibition of HCV-induced ER stress impaired WT-PGC-1{Alpha}/L-PGC-1{Alpha} upregulation along with decreased phosphorylated CREB. The correlation of hepatic mPGC-1{Alpha} with ER stress was further confirmed in mice. Overall, HCV infection upregulates both WT-PGC-1{Alpha} and L-PGC-1{Alpha} through an ER stress-mediated, phosphorylated CREB-dependent pathway, and both PGC-1{Alpha} isoforms promote HCV production in turn.

IMPORTANCE:

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{Alpha} (WT-PGC-1{Alpha}), has recently been demonstrated to link HCV infection to hepatic IR. A recent study has characterized a novel human liver-specific PGC-1{Alpha} (L-PGC-1{Alpha}), which reflects human adaption to more complex pathways. However, the effect of HCV infection on L-PGC-1{Alpha} expression and the mechanism by which HCV regulates WT-PGC-1{Alpha}/L-PGC-1{Alpha} remain unclear. In this study, we showed that HCV infection upregulated both WT-PGC-1{Alpha} and L-PGC-1{Alpha}, which further promoted HCV production. WT-PGC-1{Alpha} upregulation was mediated by CREB phosphorylation, whereas L-PGC-1{Alpha} upregulation was mediated by CREB phosphorylation and FoxO1 dephosphorylation. HCV-induced ER stress mediated WT-PGC-1{Alpha}/L-PGC-1{Alpha} upregulation and CREB phosphorylation. Overall, this study provides new insights into the mechanism by which HCV upregulates WT-PGC-1{Alpha}/L-PGC-1{Alpha} and highlights the novel intervention of HCV-ER stress-PGC-1{Alpha} signaling for HCV therapy and HCV-induced IR therapy.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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Endoplasmic reticulum stress links hepatitis C virus RNA replication to wild-type PGC-1{Alpha}/liver-specific PGC-1{Alpha} upregulation.. Global Medical Discovery