TY - JOUR
T1 - Intracellular Accumulation of IFN-λ4 Induces ER Stress and Results in Anti-Cirrhotic but Pro-HCV Effects
AU - Onabajo, Olusegun O.
AU - Wang, Fang
AU - Lee, Mei Hsuan
AU - Florez-Vargas, Oscar
AU - Obajemu, Adeola
AU - Tanikawa, Chizu
AU - Vargas, Joselin M.
AU - Liao, Shu Fen
AU - Song, Ci
AU - Huang, Yu Han
AU - Shen, Chen Yang
AU - Banday, A. Rouf
AU - O’Brien, Thomas R.
AU - Hu, Zhibin
AU - Matsuda, Koichi
AU - Prokunina-Olsson, Ludmila
N1 - Funding Information:
This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, US National Cancer Institute, research grants from the Ministry of
Funding Information:
We thank the Cancer Genomics Research Laboratory (DCEG/NCI) for help with RNA-seq and cell line authentication. We acknowledge all of the collaborators for REVEAL-II cohort: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan: Chung-Feng Huang, Chia-Yen Dai, Jee-Fu Huang, Ming-Lun Yeh, Ching-I Huang, Ming-Lung Yu, Wan-Long Chuang; Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan: Hsueh-Chou Lai, Wen-Pang Su, Jung-Ta Kao, Sheng-Hung Chen, Po-Heng Chuang, Cheng-Yuan Peng; Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan: Chun-Yen Lin, Wen-Juei Jeng, I-Shyan Sheen; Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan: Chen-Hua Liu, Chun-Jen Liu, Hung-Chih Yang, Chieh-Chang Chen, Shih-Jer Hsu, Jia-Horng Kao; Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan: Jing-Houng Wang, Kwong-Ming Kee, Sheng-Nan Lu; Academia Sinica, Taipei, Taiwan: Hwai-I Yang, Chien-Jen Chen; Global Health Economics and Outcomes Research, Bristol Myers-Squibb, Princeton, NJ, USA: Yong Yuan.
Publisher Copyright:
© Copyright © 2021 Onabajo, Wang, Lee, Florez-Vargas, Obajemu, Tanikawa, Vargas, Liao, Song, Huang, Shen, Banday, O’Brien, Hu, Matsuda and Prokunina-Olsson.
PY - 2021/8
Y1 - 2021/8
N2 - IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (VLDLR), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.
AB - IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (VLDLR), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.
KW - ER stress
KW - HCC (hepatocellular carcinoma)
KW - HCV (Hepatitis C)
KW - IFNL4
KW - liver cirrhosis
UR - http://www.scopus.com/inward/record.url?scp=85114296441&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85114296441&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.692263
DO - 10.3389/fimmu.2021.692263
M3 - Article
C2 - 34497603
AN - SCOPUS:85114296441
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 692263
ER -
