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

• Published in: Scientific reports 2016-03, Vol.6 (1), p.22487-22487, Article 22487
• Main Authors: Chusri, Pattranuch, Kumthip, Kattareeya, Hong, Jian, Zhu, Chuanlong, Duan, Xiaoqiong, Jilg, Nikolaus, Fusco, Dahlene N., Brisac, Cynthia, Schaefer, Esperance A., Cai, Dachuan, Peng, Lee F., Maneekarn, Niwat, Lin, Wenyu, Chung, Raymond T.
• Format: Article
• Language: English
• Subjects: 631/326/596/2553; 692/4020/4021/234/2513/1551; 96/95; Activating Transcription Factor 6 - genetics; Cell Line, Tumor; eIF-2 Kinase - genetics; Endoplasmic Reticulum Stress - physiology; Endoribonucleases - antagonists & inhibitors; Endoribonucleases - genetics; Endoribonucleases - metabolism; Hepacivirus - metabolism; Humanities and Social Sciences; Humans; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; multidisciplinary; NF-kappa B - metabolism; Oxidative Stress - physiology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Reactive Oxygen Species - metabolism; RNA Interference; RNA, Small Interfering - genetics; Science; Transforming Growth Factor beta1 - metabolism; Unfolded Protein Response - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep22487

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.