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Hepatitis E is usually asymptomatic and self-limiting but it can become chronic in immunocompromised patients and is associated with increased fulminant hepatic failure and mortality rates in pregnant women. HEV genome encodes three proteins including the ORF2 protein that is the viral capsid protein. Interestingly, HEV produces 3 isoforms of the ORF2 capsid protein which are partitioned in different subcellular compartments and perform distinct functions in the HEV lifecycle. Notably, the infectious ORF2 (ORF2i) protein is the structural component of virions, whereas the genome-free secreted and glycosylated ORF2 proteins likely act as a humoral immune decoy. Here, by using a series of ORF2 capsid protein mutants expressed in the infectious genotype 3 p6 HEV strain as well as chimeras between ORF2 and the CD4 glycoprotein, we demonstrated how an Arginine-Rich Motif (ARM) located in the ORF2 N-terminal region controls the fate and functions of ORF2 isoforms. We showed that the ARM controls ORF2 nuclear translocation likely to promote regulation of host antiviral responses. This motif also regulates the dual topology and functionality of ORF2 signal peptide, leading to the production of either cytosolic infectious ORF2i or reticular non-infectious glycosylated ORF2 forms. It serves as maturation site of glycosylated ORF2 by furin, and promotes ORF2-host cell membrane interactions. The identification of ORF2 ARM as a unique central regulator of the HEV lifecycle uncovers how viruses settle strategies to condense their genetic information and hijack cellular processes.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010798","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T13:58:38Z","timestamp":1661435918000},"page":"e1010798","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["An Arginine-Rich Motif in the ORF2 capsid protein regulates the hepatitis E virus lifecycle and interactions with the host cell"],"prefix":"10.1371","volume":"18","author":[{"given":"K\u00e9vin","family":"Hervouet","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Ferri\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maliki","family":"Ankavay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Montpellier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charline","family":"Camuzet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Alexandre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A\u00efcha","family":"Demb\u00e9l\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0075-6417","authenticated-orcid":true,"given":"C\u00e9cile","family":"Lecoeur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold Thomas","family":"Foe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy","family":"Bouquet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thibaut","family":"Vausselin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0105-5196","authenticated-orcid":true,"given":"Jean-Michel","family":"Saliou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Salom\u00e9-Desnoulez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2936-2411","authenticated-orcid":true,"given":"Alexandre","family":"Vandeputte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Marsollier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0991-7344","authenticated-orcid":true,"given":"Priscille","family":"Brodin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marl\u00e8ne","family":"Dreux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-9271","authenticated-orcid":true,"given":"Yves","family":"Rouill\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Dubuisson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8388-4662","authenticated-orcid":true,"given":"C\u00e9cile-Marie","family":"Aliouat-Denis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2136-5178","authenticated-orcid":true,"given":"Laurence","family":"Cocquerel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"key":"ppat.1010798.ref001","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3390\/v11070617","article-title":"The 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Feng","year":"2013","journal-title":"Nature"},{"key":"ppat.1010798.ref005","first-page":"8","article-title":"Role of Envelopment in the HEV Life Cycle","author":"X Yin","year":"2016","journal-title":"Viruses"},{"key":"ppat.1010798.ref006","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/0042-6822(91)90760-9","article-title":"Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome","volume":"185","author":"AW Tam","year":"1991","journal-title":"Virology"},{"key":"ppat.1010798.ref007","doi-asserted-by":"crossref","first-page":"719","DOI":"10.3390\/v11080719","article-title":"Hepatitis E Virus Replication","volume":"11","author":"R LeDesma","year":"2019","journal-title":"Viruses"},{"key":"ppat.1010798.ref008","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nrgastro.2017.150","article-title":"Hepatitis E virus: advances and challenges","volume":"15","author":"I Nimgaonkar","year":"2018","journal-title":"Nat. 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Dong","year":"2012","journal-title":"Hepatology"},{"key":"ppat.1010798.ref019","first-page":"1","article-title":"HEV ORF3 downregulates TLR7 to inhibit the generation of type I interferon via impairment of multiple signaling pathways","volume":"8","author":"Q Lei","year":"2018","journal-title":"Sci Rep"},{"key":"ppat.1010798.ref020","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.3748\/wjg.v24.i20.2173","article-title":"Effects of hepatitis E virus infection on interferon production via ISG15","volume":"24","author":"M Wang","year":"2018","journal-title":"World J Gastroentero"},{"key":"ppat.1010798.ref021","first-page":"1","article-title":"The ORF3 Protein of Genotype 1 Hepatitis E Virus Suppresses TLR3-induced NF-\u03baB Signaling via TRADD and RIP1","author":"M He","year":"2016","journal-title":"Sci Rep"},{"key":"ppat.1010798.ref022","doi-asserted-by":"crossref","first-page":"8696","DOI":"10.1128\/JVI.01228-14","article-title":"Enhancement of Interferon Induction by ORF3 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Demangel","year":"2018","journal-title":"Biology of the cell \/ under the auspices of the European Cell Biology Organization"},{"key":"ppat.1010798.ref026","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nrd3699","article-title":"The biology and therapeutic targeting of the proprotein convertases","volume":"11","author":"NG Seidah","year":"2012","journal-title":"Nat Rev Drug Discov"},{"key":"ppat.1010798.ref027","doi-asserted-by":"crossref","first-page":"108254","DOI":"10.1016\/j.celrep.2020.108254","article-title":"Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects","volume":"33","author":"Y-W Cheng","year":"2020","journal-title":"Cell Reports"},{"key":"ppat.1010798.ref028","doi-asserted-by":"crossref","first-page":"e1003056","DOI":"10.1371\/journal.ppat.1003056","article-title":"Three-dimensional architecture and biogenesis of membrane structures associated with hepatitis C virus 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