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000302284 1001_ $$0P:(DE-HGF)0$$aFu, Rebecca$$b0
000302284 245__ $$aIntegrin beta 1 facilitates non-enveloped hepatitis E virus cell entry through the recycling endosome.
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000302284 520__ $$aHepatitis E virus (HEV) is a major cause of acute hepatitis and mainly transmitted faecal-orally. HEV particles present in faeces are naked (nHEV), whereas those found in the blood are quasi-enveloped (eHEV) with a cell-derived lipid membrane. Despite its global health impact, the cellular life cycle of HEV remains poorly understood, particularly regarding the mechanisms of viral entry into host cells. To address this knowledge gap, we develop a high content RNA-FISH-based imaging assay that allows for the investigation of the entry pathways of both naked and quasi-enveloped HEV particles. Surprisingly, we find that integrin α3, previously implicated in nHEV cell entry, is not expressed in the cell types that are most permissive for HEV infection. Instead, we identify integrin β1 (ITGB1) pairing with different α-integrins as the key player mediating nHEV cell entry. Our results indicate that the interaction of nHEV with ITGB1 facilitates entry through Rab11-positive recycling endosomes. In contrast, eHEV particles do not interact with ITGB1 and enter cells using a classical endocytic route via Rab5a-positive early endosomes. The entry of both types of HEV particles requires endosomal acidification and proteolytic cleavage by lysosomal cathepsins, which ultimately results in delivery of the HEV genome to the cytoplasm.
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000302284 650_7 $$2NLM Chemicals$$aIntegrin beta1
000302284 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$arab5 GTP-Binding Proteins
000302284 650_7 $$2NLM Chemicals$$aItgb1 protein, human
000302284 650_7 $$0EC 3.6.1.-$$2NLM Chemicals$$arab11 protein
000302284 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$arab GTP-Binding Proteins
000302284 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aCathepsins
000302284 650_2 $$2MeSH$$aEndosomes: metabolism
000302284 650_2 $$2MeSH$$aEndosomes: virology
000302284 650_2 $$2MeSH$$aVirus Internalization
000302284 650_2 $$2MeSH$$aHumans
000302284 650_2 $$2MeSH$$aHepatitis E virus: physiology
000302284 650_2 $$2MeSH$$aHepatitis E virus: genetics
000302284 650_2 $$2MeSH$$aIntegrin beta1: metabolism
000302284 650_2 $$2MeSH$$aIntegrin beta1: genetics
000302284 650_2 $$2MeSH$$aHepatitis E: virology
000302284 650_2 $$2MeSH$$aHepatitis E: metabolism
000302284 650_2 $$2MeSH$$arab5 GTP-Binding Proteins: metabolism
000302284 650_2 $$2MeSH$$arab GTP-Binding Proteins: metabolism
000302284 650_2 $$2MeSH$$aHEK293 Cells
000302284 650_2 $$2MeSH$$aCathepsins: metabolism
000302284 650_2 $$2MeSH$$aLysosomes: metabolism
000302284 650_2 $$2MeSH$$aCell Line
000302284 7001_ $$aJordan, Paula$$b1
000302284 7001_ $$aEngels, Zoe$$b2
000302284 7001_ $$aWeihs, Jasmin Alara$$b3
000302284 7001_ $$aMürle, Josias$$b4
000302284 7001_ $$00000-0002-2347-8782$$aChi, Huanting$$b5
000302284 7001_ $$00000-0002-5364-2686$$aBurbano de Lara, Sebastian$$b6
000302284 7001_ $$0P:(DE-He78)1c49e2bc4134e93b5dc7d9845e30c039$$aHelm, Barbara$$b7$$udkfz
000302284 7001_ $$aKlöhn, Mara$$b8
000302284 7001_ $$aHu, Jungen$$b9
000302284 7001_ $$aFreistaedter, Andrew$$b10
000302284 7001_ $$00000-0002-1195-055X$$aBoettler, Tobias$$b11
000302284 7001_ $$0P:(DE-He78)2fb2bd9048a3777dddc4cb89b115c187$$aBinder, Marco$$b12$$udkfz
000302284 7001_ $$0P:(DE-He78)860df4ab16c373fb28a815dcd81107a6$$aKlingmüller, Ursula$$b13$$udkfz
000302284 7001_ $$aSteinmann, Eike$$b14
000302284 7001_ $$00000-0002-9966-1452$$aLozach, Pierre-Yves$$b15
000302284 7001_ $$00000-0002-6490-4602$$aTubiana, Thibault$$b16
000302284 7001_ $$00000-0003-1450-806X$$aLemon, Stanley M$$b17
000302284 7001_ $$00000-0003-2293-3592$$aDao Thi, Viet Loan$$b18
000302284 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-025-61071-y$$gVol. 16, no. 1, p. 5403$$n1$$p5403$$tNature Communications$$v16$$x2041-1723$$y2025
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