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

Autor:	Onabajo OO; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States., Wang F; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States., Lee MH; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan., Florez-Vargas O; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States., Obajemu A; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States., Tanikawa C; Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Vargas JM; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States., Liao SF; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.; Institute of Statistical Science, Academia Sinica, Taipei, Taiwan., Song C; Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China., Huang YH; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan., Shen CY; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan., Banday AR; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States., O'Brien TR; Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States., Hu Z; Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China., Matsuda K; Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan., Prokunina-Olsson L; Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Aug 23; Vol. 12, pp. 692263. Date of Electronic Publication: 2021 Aug 23 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.692263
Abstrakt:	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. Competing Interests: TO’B and LP-O are co-inventors on IFN-λ4-related patents issued to NCI/NIH and receive royalties for antibodies for IFN-λ4 detection. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Onabajo, Wang, Lee, Florez-Vargas, Obajemu, Tanikawa, Vargas, Liao, Song, Huang, Shen, Banday, O’Brien, Hu, Matsuda and Prokunina-Olsson.)
Databáze:	MEDLINE
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