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EIF4H and YBX1 are essential host factors for hepatitis E virus replication and pathogenesis.

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Title: EIF4H and YBX1 are essential host factors for hepatitis E virus replication and pathogenesis.
Authors: Ju, Xiaohui1,2, Dong, Lin1, Liu, Tianxu3, Zhang, Fan4, Sun, Xuege5, Schwoerer, Michael P.6, Ren, Wenlin1, Gong, Mingli1,7, Ploss, Alexander6, Qin, Wei5, Wu, Xianfang4 WUX4@ccf.org, Wang, Lin3 lin_wang@pku.edu.cn, Ding, Qiang1,8 qding@tsinghua.edu.cn
Source: Proceedings of the National Academy of Sciences of the United States of America. 3/10/2026, Vol. 123 Issue 10, p1-11. 27p.
Subjects: Hepatitis E virus, Proteins, Virology, Antiviral agents
Abstract: Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide, responsible for approximately 20 million infections annually. Despite the availability of a vaccine in China, no direct-acting antivirals are approved, and host factors required for HEV replication remain poorly defined. Here, using a genome-wide CRISPR/Cas9 knockout screen in a replicon system, we identified Eukaryotic Translation Initiation Factor 4H (EIF4H) and Y-Box Binding Protein 1 (YBX1) as essential host factors for HEV replication and pathogenesis. Knockout of either factor markedly impaired replication of HEV genotypes 1, 3, and 4, as well as HEV infection and production in hepatocellular carcinoma cells and human induced pluripotent stem cell-derived hepatocyte-like cells, while leaving SARS-CoV-2, hepatitis B virus, hepatitis C virus, and Zika virus unaffected, underscoring their HEV-specific roles. Mechanistically, EIF4H interacts with ORF1 via its methyltransferase-Y-papain-like protease region, and EIF4H deficiency alters the composition of the ORF1 -associated replication complex. By contrast, YBX1 is dispensable for ORF1 translation and RNA binding but is specifically required for ORF1 proteolytic processing, a prerequisite for assembling a functional replication machinery. EIF4H knockout rats and liver-specific YBX1 knockout rats were largely resistant to rat HEV-C1 infection, showing profound reductions in viral shedding, suppressed hepatic and intestinal viral loads, and protection from liver pathology. Together, our findings establish EIF4H and YBX1 as essential host factors for HEV infection and pathogenesis and reveal potential targets for antiviral intervention. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: EIF4H and YBX1 are essential host factors for hepatitis E virus replication and pathogenesis.
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  Data: <searchLink fieldCode="AR" term="%22Ju%2C+Xiaohui%22">Ju, Xiaohui</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Dong%2C+Lin%22">Dong, Lin</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Liu%2C+Tianxu%22">Liu, Tianxu</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Zhang%2C+Fan%22">Zhang, Fan</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Sun%2C+Xuege%22">Sun, Xuege</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Schwoerer%2C+Michael+P%2E%22">Schwoerer, Michael P.</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Ren%2C+Wenlin%22">Ren, Wenlin</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Gong%2C+Mingli%22">Gong, Mingli</searchLink><relatesTo>1,7</relatesTo><br /><searchLink fieldCode="AR" term="%22Ploss%2C+Alexander%22">Ploss, Alexander</searchLink><relatesTo>6</relatesTo><br /><searchLink fieldCode="AR" term="%22Qin%2C+Wei%22">Qin, Wei</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Wu%2C+Xianfang%22">Wu, Xianfang</searchLink><relatesTo>4</relatesTo><i> WUX4@ccf.org</i><br /><searchLink fieldCode="AR" term="%22Wang%2C+Lin%22">Wang, Lin</searchLink><relatesTo>3</relatesTo><i> lin_wang@pku.edu.cn</i><br /><searchLink fieldCode="AR" term="%22Ding%2C+Qiang%22">Ding, Qiang</searchLink><relatesTo>1,8</relatesTo><i> qding@tsinghua.edu.cn</i>
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  Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 3/10/2026, Vol. 123 Issue 10, p1-11. 27p.
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  Data: <searchLink fieldCode="DE" term="%22Hepatitis+E+virus%22">Hepatitis E virus</searchLink><br /><searchLink fieldCode="DE" term="%22Proteins%22">Proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Virology%22">Virology</searchLink><br /><searchLink fieldCode="DE" term="%22Antiviral+agents%22">Antiviral agents</searchLink>
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  Data: Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide, responsible for approximately 20 million infections annually. Despite the availability of a vaccine in China, no direct-acting antivirals are approved, and host factors required for HEV replication remain poorly defined. Here, using a genome-wide CRISPR/Cas9 knockout screen in a replicon system, we identified Eukaryotic Translation Initiation Factor 4H (EIF4H) and Y-Box Binding Protein 1 (YBX1) as essential host factors for HEV replication and pathogenesis. Knockout of either factor markedly impaired replication of HEV genotypes 1, 3, and 4, as well as HEV infection and production in hepatocellular carcinoma cells and human induced pluripotent stem cell-derived hepatocyte-like cells, while leaving SARS-CoV-2, hepatitis B virus, hepatitis C virus, and Zika virus unaffected, underscoring their HEV-specific roles. Mechanistically, EIF4H interacts with ORF1 via its methyltransferase-Y-papain-like protease region, and EIF4H deficiency alters the composition of the ORF1 -associated replication complex. By contrast, YBX1 is dispensable for ORF1 translation and RNA binding but is specifically required for ORF1 proteolytic processing, a prerequisite for assembling a functional replication machinery. EIF4H knockout rats and liver-specific YBX1 knockout rats were largely resistant to rat HEV-C1 infection, showing profound reductions in viral shedding, suppressed hepatic and intestinal viral loads, and protection from liver pathology. Together, our findings establish EIF4H and YBX1 as essential host factors for HEV infection and pathogenesis and reveal potential targets for antiviral intervention. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2529289123
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        Text: English
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      – SubjectFull: Virology
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