Intracellular Accumulation of IFN-λ4 Induces ER Stress and Results in Anti-Cirrhotic but Pro-HCV Effects

• Published in: Frontiers in immunology Vol. 12; p. 692263
• Main Authors: Onabajo, Olusegun O, Wang, Fang, Lee, Mei-Hsuan, Florez-Vargas, Oscar, Obajemu, Adeola, Tanikawa, Chizu, Vargas, Joselin M, Liao, Shu-Fen, Song, Ci, Huang, Yu-Han, Shen, Chen-Yang, Banday, A Rouf, O'Brien, Thomas R, Hu, Zhibin, Matsuda, Koichi, Prokunina-Olsson, Ludmila
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 23.08.2021
• Subjects: Adult; Apoptosis; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - virology; Case-Control Studies; Cell Proliferation; Databases, Factual; Endoplasmic Reticulum Stress; ER stress; Female; Genetic Predisposition to Disease; HCC (hepatocellular carcinoma); HCV (Hepatitis C); Hep G2 Cells; Hepatitis C - genetics; Hepatitis C - metabolism; Hepatitis C - virology; Humans; IFNL4; Immunology; Interferons - genetics; Interleukins - genetics; Interleukins - metabolism; Japan; Liver - metabolism; Liver - pathology; liver cirrhosis; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Cirrhosis - prevention & control; Liver Cirrhosis - virology; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - virology; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Protective Factors; Risk Assessment; Risk Factors; Taiwan; Japan; Taiwan; ER stress; HCC (hepatocellular carcinoma); IFNL4; liver cirrhosis; HCV (Hepatitis C)
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.692263

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 polymorphisms represented by the genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. 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. 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 ( ), 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 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.