Hepatitis B virus (HBV) infection can cause liver disease and lead to hepatocellular carcinoma (HCC). To better understand the factors involved in viral infection and pathogenesis and to develop novel therapies, it is crucial to investigate virus-host interactions. HBV infection has been shown to increase the expression of the unconventional prefoldin RPB5 interactor (URI1), a cellular protein that promotes liver tumorigenesis and HCC metastasis. Our study investigated the role of URI1 in HBV infection in vitro. Although previous reports have suggested that URI1 may act as an HBV restriction factor, our results showed that URI1 silencing or overexpression did not affect HBV replication in HepG2-NTCP cells. In primary human hepatocytes, URI1 knockdown modestly reduced HBV markers but did not significantly alter acute infection. Supporting the premise that URI1 is a promising therapeutic target for HCC, our findings show that URI1 knockdown does not enhance HBV infection in an acute infection model. This suggests that URI1 may be a viable therapeutic target for patients with HBV-associated HCC without increasing HBV-related complications.

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic

See more in PubMed

Schlaak JF. Current Therapy of Chronic Viral Hepatitis B, C and D. J Pers Med. 2023;13:964. PubMed PMC

Burén S, Gomes AL, Teijeiro A, Fawal M-A, Yilmaz M, Tummala KS, et al. Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms. Cancer Cell. 2016;30:290–307. PubMed

Tummala KS, Gomes AL, Yilmaz M, Graña O, Bakiri L, Ruppen I, et al. Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell. 2014;26:826–839. PubMed

Tsuchiya H, Amisaki M, Takenaga A, Honjo S, Fujiwara Y, Shiota G. HBx and c-MYC cooperate to induce URI1 expression in HBV-Related Hepatocellular Carcinoma. Int J Mol Sci. 2019;20. PubMed PMC

Gomes AL, Teijeiro A, Burén S, Tummala KS, Yilmaz M, Waisman A, et al. Metabolic Inflammation-Associated IL-17A Causes Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma. Cancer Cell. 2016;30:161–75. PubMed

Zhang J, Pan Y-F, Ding Z-W, Yang G-Z, Tan Y-X, Yang C, et al. RMP promotes venous metastases of hepatocellular carcinoma through promoting IL-6 transcription. Oncogene. 2015;34:1575–83. PubMed

Zhou W, Wang Q, Xu Y, Jiang J, Guo J, Yu H, et al. RMP promotes epithelial-mesenchymal transition through NF-κB/CSN2/Snail pathway in hepatocellular carcinoma. Oncotarget. 2017;8:40373–88. PubMed PMC

Ding Z, Pan Y, Shang T, Jiang T, Lin Y, Yang C, et al. URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers. Nat Commun. 2023;14:6269. PubMed PMC

Xu Y, Ji Y, Li X, Ding J, Chen L, Huang Y, et al. URI1 suppresses irradiation-induced reactive oxygen species (ROS) by activating autophagy in hepatocellular carcinoma cells. Int J Biol Sci. 2021;17:3091–103. PubMed PMC

Wang Q, Xu Y, Zhou W, Zhong L, Wen Z, Yu H, et al. The Viral Oncoprotein HBx of Hepatitis B virus Promotes the Growth of Hepatocellular Carcinoma Through Cooperating with the Cellular Oncoprotein RMP. Int J Biol Sci. 2014;10:1181–92. PubMed PMC

Mederacke I, Schwabe RF. NAD(+) supplementation as a novel approach to cURIng HCC? Cancer Cell. 2014;26:777–8. PubMed

Dorjsuren D, Lin Y, Wei W, Yamashita T, Nomura T, Hayashi N, et al. RMP, a novel RNA polymerase II subunit 5-interacting protein, counteracts transactivation by hepatitis B virus X protein. Mol Cell Biol. 1998;18:7546–55. PubMed PMC

Zhou Q, Huang F, Chen L, Chen E, Bai L, Cheng X, et al. RPB5-Mediating protein suppresses Hepatitis B Virus (HBV) transcription and replication by counteracting the transcriptional activation of Hepatitis B virus X protein in HBV Replication Mouse Model. Jundishapur J Microbiol. 2015;8:e21936. PubMed PMC

Lee GS, Purdy MA, Choi Y. Cell Culture systems for studying Hepatitis B and Hepatitis D Virus infections. Life. 2023;13:1527. PubMed PMC

Olsavsky KM, Page JL, Johnson MC, Zarbl H, Strom SC, Omiecinski CJ. Gene expression profiling and differentiation assessment in primary human hepatocyte cultures, established hepatoma cell lines, and human liver tissues. Toxicol Appl Pharmacol. 2007;222:42–56. PubMed PMC

Lubyova B, Hodek J, Zabransky A, Prouzova H, Hubalek M, Hirsch I, et al. PRMT5: a novel regulator of Hepatitis B virus replication and an arginine methylase of HBV core. PLoS ONE. 2017;12:e0186982. PubMed PMC

Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, et al. IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest. 2012;122:529–37. PubMed PMC

Pollicino T, Belloni L, Raffa G, Pediconi N, Squadrito G, Raimondo G, et al. Hepatitis B Virus replication is regulated by the Acetylation Status of Hepatitis B Virus cccDNA-Bound H3 and H4 histones. Gastroenterology. 2006;130:823–37. PubMed

Kornyeyev D, Ramakrishnan D, Voitenleitner C, Livingston CM, Xing W, Hung M et al. Spatiotemporal analysis of Hepatitis B Virus X protein in primary human hepatocytes. J Virol. 2019;93. PubMed PMC

Slagle BL, Andrisani OM, Bouchard MJ, Lee CGL, Ou J-HJ, Siddiqui A. Technical standards for hepatitis B virus X protein (HBx) research. Hepatology. 2015;61:1416–24. PubMed PMC