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

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Chusri, Pattranuch
Kumthip, Kattareeya
Hong, Jian
Zhu, Chuanlong
Duan, Xiaoqiong
Brisac, Cynthia
Cai, Dachuan
Peng, Lee F.
Maneekarn, Niwat
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/srep22487Metadata
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Chusri, P., K. Kumthip, J. Hong, C. Zhu, X. Duan, N. Jilg, D. N. Fusco, et al. 2016. “HCV induces transforming growth factor β1 through activation of endoplasmic reticulum stress and the unfolded protein response.” Scientific Reports 6 (1): 22487. doi:10.1038/srep22487. http://dx.doi.org/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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772380/pdf/Terms of Use
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