Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome
Abstract Hepatitis E virus (HEV) is a major cause of acute hepatitis and mainly transmitted faecal-orally. HEV particles present in faeces are naked (nHEV), whereas those found in the blood are quasi-enveloped (eHEV) with a cell-derived lipid membrane. Despite its global health impact, the cellular...
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61071-y |
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| author | Rebecca Fu Paula Jordan Zoe Engels Jasmin Alara Weihs Josias Mürle Huanting Chi Sebastian Burbano de Lara Barbara Helm Mara Klöhn Jungen Hu Andrew Freistaedter Tobias Boettler Marco Binder Ursula Klingmüller Eike Steinmann Pierre-Yves Lozach Thibault Tubiana Stanley M. Lemon Viet Loan Dao Thi |
| author_facet | Rebecca Fu Paula Jordan Zoe Engels Jasmin Alara Weihs Josias Mürle Huanting Chi Sebastian Burbano de Lara Barbara Helm Mara Klöhn Jungen Hu Andrew Freistaedter Tobias Boettler Marco Binder Ursula Klingmüller Eike Steinmann Pierre-Yves Lozach Thibault Tubiana Stanley M. Lemon Viet Loan Dao Thi |
| author_sort | Rebecca Fu |
| collection | DOAJ |
| description | Abstract Hepatitis E virus (HEV) is a major cause of acute hepatitis and mainly transmitted faecal-orally. HEV particles present in faeces are naked (nHEV), whereas those found in the blood are quasi-enveloped (eHEV) with a cell-derived lipid membrane. Despite its global health impact, the cellular life cycle of HEV remains poorly understood, particularly regarding the mechanisms of viral entry into host cells. To address this knowledge gap, we develop a high content RNA-FISH-based imaging assay that allows for the investigation of the entry pathways of both naked and quasi-enveloped HEV particles. Surprisingly, we find that integrin α3, previously implicated in nHEV cell entry, is not expressed in the cell types that are most permissive for HEV infection. Instead, we identify integrin β1 (ITGB1) pairing with different α-integrins as the key player mediating nHEV cell entry. Our results indicate that the interaction of nHEV with ITGB1 facilitates entry through Rab11-positive recycling endosomes. In contrast, eHEV particles do not interact with ITGB1 and enter cells using a classical endocytic route via Rab5a-positive early endosomes. The entry of both types of HEV particles requires endosomal acidification and proteolytic cleavage by lysosomal cathepsins, which ultimately results in delivery of the HEV genome to the cytoplasm. |
| format | Article |
| id | doaj-art-48a92abeba284c918d151f88840a87c2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-48a92abeba284c918d151f88840a87c22025-08-20T03:27:18ZengNature PortfolioNature Communications2041-17232025-06-0116111810.1038/s41467-025-61071-yIntegrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosomeRebecca Fu0Paula Jordan1Zoe Engels2Jasmin Alara Weihs3Josias Mürle4Huanting Chi5Sebastian Burbano de Lara6Barbara Helm7Mara Klöhn8Jungen Hu9Andrew Freistaedter10Tobias Boettler11Marco Binder12Ursula Klingmüller13Eike Steinmann14Pierre-Yves Lozach15Thibault Tubiana16Stanley M. Lemon17Viet Loan Dao Thi18Schaller Research Group, Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty HeidelbergSchaller Research Group, Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty HeidelbergSchaller Research Group, Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty HeidelbergSchaller Research Group, Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty HeidelbergSchaller Research Group, Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty HeidelbergGerman Centre for Infection Research (DZIF), Partner Site HeidelbergDivision of Systems Biology of Signal Transduction (B200), German Cancer Research Center (DKFZ)Division of Systems Biology of Signal Transduction (B200), German Cancer Research Center (DKFZ)Department of Molecular and Medical Virology, Ruhr University BochumSchaller Research Group, Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty HeidelbergSchaller Research Group, Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty HeidelbergDepartment of Medicine II, Medical Center – University of FreiburgResearch Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (D430), German Cancer Research Center (DKFZ)Division of Systems Biology of Signal Transduction (B200), German Cancer Research Center (DKFZ)Department of Molecular and Medical Virology, Ruhr University BochumUniv. Lyon, INRAE, EPHE, IVPCInstitute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, CEA, CNRSDepartments of Medicine and Microbiology & Immunology, The University of North Carolina at Chapel HillSchaller Research Group, Department of Infectious Diseases, Virology, Heidelberg University, Medical Faculty HeidelbergAbstract Hepatitis E virus (HEV) is a major cause of acute hepatitis and mainly transmitted faecal-orally. HEV particles present in faeces are naked (nHEV), whereas those found in the blood are quasi-enveloped (eHEV) with a cell-derived lipid membrane. Despite its global health impact, the cellular life cycle of HEV remains poorly understood, particularly regarding the mechanisms of viral entry into host cells. To address this knowledge gap, we develop a high content RNA-FISH-based imaging assay that allows for the investigation of the entry pathways of both naked and quasi-enveloped HEV particles. Surprisingly, we find that integrin α3, previously implicated in nHEV cell entry, is not expressed in the cell types that are most permissive for HEV infection. Instead, we identify integrin β1 (ITGB1) pairing with different α-integrins as the key player mediating nHEV cell entry. Our results indicate that the interaction of nHEV with ITGB1 facilitates entry through Rab11-positive recycling endosomes. In contrast, eHEV particles do not interact with ITGB1 and enter cells using a classical endocytic route via Rab5a-positive early endosomes. The entry of both types of HEV particles requires endosomal acidification and proteolytic cleavage by lysosomal cathepsins, which ultimately results in delivery of the HEV genome to the cytoplasm.https://doi.org/10.1038/s41467-025-61071-y |
| spellingShingle | Rebecca Fu Paula Jordan Zoe Engels Jasmin Alara Weihs Josias Mürle Huanting Chi Sebastian Burbano de Lara Barbara Helm Mara Klöhn Jungen Hu Andrew Freistaedter Tobias Boettler Marco Binder Ursula Klingmüller Eike Steinmann Pierre-Yves Lozach Thibault Tubiana Stanley M. Lemon Viet Loan Dao Thi Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome Nature Communications |
| title | Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome |
| title_full | Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome |
| title_fullStr | Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome |
| title_full_unstemmed | Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome |
| title_short | Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome |
| title_sort | integrin beta 1 facilitates non enveloped hepatitis e virus cell entry through the recycling endosome |
| url | https://doi.org/10.1038/s41467-025-61071-y |
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