Endoplasmic Reticulum Stress Links Hepatitis C Virus RNA Replication to Wild-Type PGC-1α/Liver-Specific PGC-1α Upregulation

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␣) 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. 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␣ (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.

Hepatitis C virus core or NS3/4A protein expression preconditions hepatocytes against oxidative stress and endoplasmic reticulum stress

“…The UPR serves to diminish ER stress [21]. HCV infection will lead to the accumulation of viral proteins in the ER and viral protein synthesis can lead to ER stress [48,49]. Consequences of ER stress and UPR are increased mRNA levels of GRP78 (HSPA5) that acts as an inducible chaperone in the UPR and sXBP1 activation [23].…”

PGC-1α, glucose metabolism and type 2 diabetes mellitus

“…In addition, a recent study has reported that HCV infection induces PGC-1α expression and ER stress. Moreover, pharmacological induction of ER stress upregulates PGC-1α expression, and pharmacological inhibition of HCV-induced ER stress impairs PGC-1α upregulation (Yao et al 2014).…”

Cell-death-inducing DFFA-like Effector B Contributes to the Assembly of Hepatitis C Virus (HCV) Particles and Interacts with HCV NS5A

“…The specific infectivity was calculated to evaluate the efficiency of HCV assembly36, whereas the ratio of the extracellular titer to the intracellular titer was used to evaluate the level of viral particle secretion1826. Results showed that similar to siApoE, siCiDeB significantly reduced extracellular HCV specific infectivity whereas siCD81 had no effect (Fig.…”

“…To further investigate whether CIDEB is involved in the late stage of the HCV life cycle, we calculated the specific infectivity (infectious titer divided by the HCV RNA copy number) and the ratio of the extracellular HCV titer to the intracellular HCV titer, as previously described1826. The specific infectivity was calculated to evaluate the efficiency of HCV assembly36, whereas the ratio of the extracellular titer to the intracellular titer was used to evaluate the level of viral particle secretion1826.…”