TY  - JOUR
AU  - Fu, Rebecca
AU  - Jordan, Paula
AU  - Engels, Zoe
AU  - Weihs, Jasmin Alara
AU  - Mürle, Josias
AU  - Chi, Huanting
AU  - Burbano de Lara, Sebastian
AU  - Helm, Barbara
AU  - Klöhn, Mara
AU  - Hu, Jungen
AU  - Freistaedter, Andrew
AU  - Boettler, Tobias
AU  - Binder, Marco
AU  - Klingmüller, Ursula
AU  - Steinmann, Eike
AU  - Lozach, Pierre-Yves
AU  - Tubiana, Thibault
AU  - Lemon, Stanley M
AU  - Dao Thi, Viet Loan
TI  - Integrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-01303
SP  - 5403
PY  - 2025
AB  - 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.
KW  - Endosomes: metabolism
KW  - Endosomes: virology
KW  - Virus Internalization
KW  - Humans
KW  - Hepatitis E virus: physiology
KW  - Hepatitis E virus: genetics
KW  - Integrin beta1: metabolism
KW  - Integrin beta1: genetics
KW  - Hepatitis E: virology
KW  - Hepatitis E: metabolism
KW  - rab5 GTP-Binding Proteins: metabolism
KW  - rab GTP-Binding Proteins: metabolism
KW  - HEK293 Cells
KW  - Cathepsins: metabolism
KW  - Lysosomes: metabolism
KW  - Cell Line
KW  - Integrin beta1 (NLM Chemicals)
KW  - rab5 GTP-Binding Proteins (NLM Chemicals)
KW  - Itgb1 protein, human (NLM Chemicals)
KW  - rab11 protein (NLM Chemicals)
KW  - rab GTP-Binding Proteins (NLM Chemicals)
KW  - Cathepsins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40571699
DO  - DOI:10.1038/s41467-025-61071-y
UR  - https://inrepo02.dkfz.de/record/302284
ER  -