Academic Journal
The tyrosine kinase Yes1 is a druggable host factor of HEV.
| Title: | The tyrosine kinase Yes1 is a druggable host factor of HEV. |
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| Authors: | Haase JA; Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany., Baheerathan A; Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany., Zhang X; KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium., Fu RM; Schaller Research Group, Department of Infectious Diseases and Virology, Heidelberg University Hospital, Heidelberg, Germany.; Heidelberg Biosciences International Graduate School, Heidelberg University, Heidelberg, Germany., Nocke MK; Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany., Decker C; Schaller Research Group, Department of Infectious Diseases and Virology, Heidelberg University Hospital, Heidelberg, Germany.; Heidelberg Biosciences International Graduate School, Heidelberg University, Heidelberg, Germany., Dao Thi VL; Schaller Research Group, Department of Infectious Diseases and Virology, Heidelberg University Hospital, Heidelberg, Germany.; German Centre for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany., Todt D; Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany.; European Virus Bioinformatics Centre (EVBC), Jena, Germany., Neyts J; KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium., Kaptein SJF; KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, Leuven, Belgium., Steinmann E; Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany.; German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany., Kinast V; Department of Molecular and Medical Virology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany.; Department of Medical Microbiology and Virology, Carl von Ossietzky University Oldenburg, Oldenburg, Germany. |
| Source: | Hepatology communications [Hepatol Commun] 2024 Oct 17; Vol. 8 (11). Date of Electronic Publication: 2024 Oct 17 (Print Publication: 2024). |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Wolters Kluwer Health, Inc Country of Publication: United States NLM ID: 101695860 Publication Model: eCollection Cited Medium: Internet ISSN: 2471-254X (Electronic) Linking ISSN: 2471254X NLM ISO Abbreviation: Hepatol Commun Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2023- : [Philadelphia] : Wolters Kluwer Health, Inc. Original Publication: [Hoboken, NJ] : Wiley Periodicals, Inc. on behalf of the American Association for the Study of Liver Diseases, [2017]- |
| MeSH Terms: | Hepatocytes*/virology , Hepatocytes*/metabolism , Hepatitis E virus*/physiology , Hepatitis E virus*/genetics , Hepatitis E virus*/drug effects , Hepatitis E*/drug therapy , Hepatitis E*/virology , Proto-Oncogene Proteins c-yes*/genetics , Proto-Oncogene Proteins c-yes*/metabolism, Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Humans ; Animals ; Rats ; Rats, Nude ; Disease Models, Animal |
| Abstract: | Background: HEV is a positive-sense, single-stranded RNA virus of the Hepeviridae family. Although HEV accounts for more than 3 million symptomatic cases of viral hepatitis per year, specific anti-HEV therapy and knowledge about HEV pathogenesis are scarce. Methods: To gain a deeper understanding of the HEV infectious cycle and guide the development of novel antiviral strategies, we here used an RNAi mini screen targeting a selection of kinases, including mitogen-activated protein kinases, receptor tyrosine kinases, and Src-family kinases. Further, we used state-of-the-art HEV infection models, including primary human hepatocytes and athymic nude rats. Results: Upon knockdown of the Src-family kinase Yes1, a significant reduction of HEV susceptibility could be observed, suggesting an important role of Yes1 in the HEV infectious cycle. Selective inhibition of Yes1 kinase activity resulted in significant inhibition of HEV infection in hepatoma cells and primary human hepatocytes, as well as in a rat HEV in vivo model system. Subsequent analysis of Y1KI during the HEV infectious life cycle indicated a role of Yes1 kinase activity in the early onset of HEV infection. Conclusions: We identified the dependence of HEV on Yes1 signaling, which may contribute to the so far scarce knowledge of HEV's pathogenesis in the future. Moreover, we provide Y1KI as a novel antiviral drug candidate specifically targeting an HEV host factor. (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.) |
| References: | Rein DB, Stevens GA, Theaker J, Wittenborn JS, Wiersma ST. The global burden of hepatitis E virus genotypes 1 and 2 in 2005. Hepatology. 2012;55:988–997. Pérez‐Gracia MT, Suay‐García B, Mateos‐Lindemann ML. Hepatitis E and pregnancy: Current state. Rev Med Virol. 2017;27:e1929. Velavan TP, Pallerla SR, Johne R, Todt D, Steinmann E, Schemmerer M, et al. Hepatitis E: An update on One Health and clinical medicine. Liver Int. 2021;41:1462–1473. Shenk T, Alwine JC. Human cytomegalovirus: Coordinating cellular stress, signaling, and metabolic pathways. Annu Rev Virol. 2014;1:355–374. Benn J, Schneider RJ. Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc Natl Acad Sci USA. 1994;91:10350–10354. Moreno-Altamirano MMB, Kolstoe SE, Sánchez-García FJ. Virus control of cell metabolism for replication and evasion of host immune responses. Front Cell Infect Microbiol. 2019;9:95. Roca Suarez AA, Testoni B, Baumert TF, Lupberger J. Nucleic acid-induced signaling in chronic viral liver disease. Front Immunol. 2020;11:624034. Mankouri J, Tedbury PR, Gretton S, Hughes ME, Griffin SDC, Dallas ML, et al. Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc Natl Acad Sci USA. 2010;107:11549–11554. Kim KH, Hong SP, Kim K, Park MJ, Kim KJ, Cheong J. HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma. Biochem Biophys Res Commun. 2007;355:883–888. Mengshol JA, Golden-Mason L, Rosen HR. Mechanisms of disease: HCV-induced liver injury. Nat Clin Pract Gastroenterol Hepatol. 2007;4:622–634. Schrader JA, Burkard TL, Brüggemann Y, Gömer A, Meister TL, Fu RM, et al. EGF receptor modulates HEV entry in human hepatocytes. Hepatology. 2023;77:2104–2117. Meister TL, Klöhn M, Steinmann E, Todt D. A cell culture model for producing high titer hepatitis E virus stocks. J Visual Exp. 2020;160:e61373. Todt D, Friesland M, Moeller N, Praditya D, Kinast V, Brüggemann Y, et al. Robust hepatitis E virus infection and transcriptional response in human hepatocytes. Proc Natl Acad Sci USA. 2020;117:1731–1741. Fan M, Luo Y, Zhang B, Wang J, Chen T, Liu B, et al. Cell division control protein 42 interacts with hepatitis E virus capsid protein and participates in hepatitis E virus infection. Front Microbiol. 2021;12:775083. Schlessinger J. New roles for Src kinases in control of cell survival and angiogenesis. Cell. 2000;100:293–296. Reinehr R, Sommerfeld A, Häussinger D. The Src family kinases: Distinct functions of c-Src, Yes, and Fyn in the liver. Biomol Concepts. 2013;4:129–142. Stein PL, Vogel H, Soriano P. Combined deficiencies of Src, Fyn, and Yes tyrosine kinases in mutant mice. Genes Dev. 1994;8:1999–2007. Aizarani N, Saviano A, Sagar, Mailly L, Durand S, Herman JS, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature. 2019;572:199–204. Shiota T, Li TC, Nishimura Y, Yoshizaki S, Sugiyama R, Shimojima M, et al. Integrin alpha3 is involved in non-enveloped hepatitis E virus infection. Virology. 2019;536:119–124. Hamanaka N, Nakanishi Y, Mizuno T, Horiguchi-Takei K, Akiyama N, Tanimura H, et al. YES1 is a targetable oncogene in cancers harboring YES1 gene amplification. Cancer Res. 2019;79:5734–5745. Shukla P, Nguyen HT, Faulk K, Mather K, Torian U, Engle RE, et al. Adaptation of a genotype 3 hepatitis E virus to efficient growth in cell culture depends on an inserted human gene segment acquired by recombination. J Virol. 2012;86:5697–5707. Korkaya H, Jameel S, Gupta D, Tyagi S, Kumar R, Zafrullah M, et al. The ORF3 protein of hepatitis E virus binds to Src homology 3 domains and activates MAPK. J Biol Chem. 2001;276:42389–42400. Fu R, Engels Z, Weihs JA, Mürle J, Klöhn M, Todt D, et al. A high-content RNA-based imaging assay reveals integrin beta 1 as a cofactor for cell entry of non-enveloped hepatitis E virus. bioRxiv. 2023. doi:10.1101/2023.10.27.564362. (PMID: 10.1101/2023.10.27.564362) Debing Y, Ramière C, Dallmeier K, Piorkowski G, Trabaud MA, Lebossé F, et al. Hepatitis E virus mutations associated with ribavirin treatment failure result in altered viral fitness and ribavirin sensitivity. J Hepatol. 2016;65:499–508. Todt D, Gisa A, Radonic A, Nitsche A, Behrendt P, Suneetha PV, et al. In vivo evidence for ribavirin-induced mutagenesis of the hepatitis E virus genome. Gut. 2016;65:1733–1743. Debing Y, Mishra N, Verbeken E, Ramaekers K, Dallmeier K, Neyts J. A rat model for hepatitis E virus. Dis Model Mech. 2016;9:1203–1210. Zhang X, Cremers N, Hendrickx S, Debing Y, Roskams T, Coelmont L, et al. Establishment of a robust rat hepatitis E virus fecal-oral infection model and validation for antiviral studies. Antiviral Res. 2023;216:105670. Summy JM, Sudol M, Eck MJ, Monteiro AN, Gatesman A, Flynn DC. Specificity in signaling by c-Yes. Front Biosci. 2003;8:s185–s205. Garmendia I, Redin E, Montuenga LM, Calvo A. YES1: A novel therapeutic target and biomarker in cancer. Mol Cancer Ther. 2022;21:1371–1380. Sudol M. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene. 1994;9:2145–2152. Pfannkuche A, Büther K, Karthe J, Poenisch M, Bartenschlager R, Trilling M, et al. c-Src is required for complex formation between the hepatitis C virus-encoded proteins NS5A and NS5B: A prerequisite for replication. Hepatology. 2011;53:1127–1136. Hirsch AJ, Medigeshi GR, Meyers HL, DeFilippis V, Früh K, Briese T, et al. The Src family kinase c-Yes is required for maturation of West Nile virus particles. J Virol. 2005;79:11943–11951. Emerson SU, Nguyen HT, Torian U, Burke D, Engle R, Purcell RH. Release of genotype 1 hepatitis E virus from cultured hepatoma and polarized intestinal cells depends on open reading frame 3 protein and requires an intact PXXP motif. J Virol. 2010;84:9059–9069. Yamada K, Takahashi M, Hoshino Y, Takahashi H, Ichiyama K, Nagashima S, et al. ORF3 protein of hepatitis E virus is essential for virion release from infected cells. J Gen Virol. 2009;90(pt 8):1880–1891. Carlin CR. Role of EGF receptor regulatory networks in the host response to viral infections. Front Cell Infect Microbiol. 2021;11:820355. Zheng K, Kitazato K, Wang Y. Viruses exploit the function of epidermal growth factor receptor. Rev Med Virol. 2014;24:274–286. Klinghoffer RA, Sachsenmaier C, Cooper JA, Soriano P. Src family kinases are required for integrin but not PDGFR signal transduction. EMBO J. 1999;18:2459–2471. Hussein HAM, Walker LR, Abdel-Raouf UM, Desouky SA, Montasser AKM, Akula SM. Beyond RGD: Virus interactions with integrins. Arch Virol. 2015;160:2669–2681. |
| Substance Nomenclature: | EC 2.7.10.2 (Proto-Oncogene Proteins c-yes) 0 (Antiviral Agents) |
| Entry Date(s): | Date Created: 20241119 Date Completed: 20241119 Latest Revision: 20260629 |
| Update Code: | 20260630 |
| PubMed Central ID: | PMC11495762 |
| DOI: | 10.1097/HC9.0000000000000553 |
| PMID: | 39560373 |
| Database: | MEDLINE |
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