HCV induces transforming growth factor β1 through activation of endoplasmic reticulum stress and the unfolded protein response

Sci Rep. 2016 Mar 1:6:22487. doi: 10.1038/srep22487.

Abstract

HCV replication disrupts normal endoplasmic reticulum (ER) function and activates a signaling network called the unfolded protein response (UPR). UPR is directed by three ER transmembrane proteins including ATF6, IRE1, and PERK. HCV increases TGF-β1 and oxidative stress, which play important roles in liver fibrogenesis. HCV has been shown to induce TGF-β1 through the generation of reactive oxygen species (ROS) and p38 MAPK, JNK, ERK1/2, and NFκB-dependent pathways. However, the relationship between HCV-induced ER stress and UPR activation with TGF-β1 production has not been fully characterized. In this study, we found that ROS and JNK inhibitors block HCV up-regulation of ER stress and UPR activation. ROS, JNK and IRE1 inhibitors blocked HCV-activated NFκB and TGF-β1 expression. ROS, ER stress, NFκB, and TGF-β1 signaling were blocked by JNK specific siRNA. Knockdown IRE1 inhibited JFH1-activated NFκB and TGF-β1 activity. Knockdown of JNK and IRE1 blunted JFH1 HCV up-regulation of NFκB and TGF-β1 activation. We conclude that HCV activates NFκB and TGF-β1 through ROS production and induction of JNK and the IRE1 pathway. HCV infection induces ER stress and the UPR in a JNK-dependent manner. ER stress and UPR activation partially contribute to HCV-induced NF-κB activation and enhancement of TGF-β1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / genetics
  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress / physiology*
  • Endoribonucleases / antagonists & inhibitors
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Hepacivirus / metabolism*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Oxidative Stress / physiology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Transforming Growth Factor beta1 / metabolism*
  • Unfolded Protein Response / physiology*
  • eIF-2 Kinase / genetics

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • NF-kappa B
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Transforming Growth Factor beta1
  • EIF2AK3 protein, human
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • JNK Mitogen-Activated Protein Kinases
  • Endoribonucleases