Phosphorylation of Ser711 Residue in the Hypervariable Region of Zoonotic Genotype 3 Hepatitis E Virus is Important for Virus Replication

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dc.contributor.authorWang, Boen
dc.contributor.authorSubramaniam, Sakthivelen
dc.contributor.authorTian, Debinen
dc.contributor.authorMahsoub, Hassan M.en
dc.contributor.authorHeffron, C. Lynnen
dc.contributor.authorMeng, Xiang-Jinen
dc.date.accessioned2024-12-19T15:35:17Zen
dc.date.available2024-12-19T15:35:17Zen
dc.date.issued2024-10-08en
dc.description.abstractHepatitis E virus (HEV) is distinct from other hepatotropic viruses because it is zoonotic. HEV-1 and HEV-2 exclusively infect humans, whereas HEV-3 and HEV-4 are zoonotic. However, the viral and/or host factors responsible for cross-species HEV transmission remain elusive. The hypervariable region (HVR) in HEV is extremely heterogenetic and is implicated in HEV adaptation. Here, we investigated the potential role of Serine phosphorylation in the HVR in HEV replication. We first analyzed HVR sequences across different HEV genotypes and identified a unique region at the N-terminus of the HVR, which is variable in the human-exclusive HEV genotypes but relatively conserved in zoonotic HEV genotypes. Using predictive tools, we identified four potential phosphorylation sites that are highly conserved in zoonotic HEV-3 and HEV-4 genomes but absent in human-exclusive HEV-1 strains. To explore the functional significance of these putative phosphorylation sites, we introduced mutations into the HEV-3 infectious clone and indicator replicon, replacing each Serine residue individually with alanine or aspartic acid, and assessed the impact of these substitutions on HEV-3 replication. We found that the phospho-blatant S711A mutant significantly reduced virus replication, whereas the phospho-mimetic S711D mutant modestly reduced virus replication. Conversely, mutations in the other three Serine residues did not significantly affect HEV-3 replication. Furthermore, we demonstrated that Ser711 phosphorylation did not alter host cell tropism of zoonotic HEV-3. In conclusion, our results showed that potential phosphorylation of the Ser711 residue significantly affects HEV-3 replication in vitro, providing new insights into the potential mechanisms of zoonotic HEV transmission.en
dc.description.notesYes, abstract only (Peer reviewed?)en
dc.description.versionPublished versionen
dc.format.extent20 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1128/mbio.02635-24en
dc.identifier.eissn2150-7511en
dc.identifier.issn2150-7511en
dc.identifier.issue11en
dc.identifier.orcidMeng, Xiang-Jin [0000-0002-2739-1334]en
dc.identifier.pmid39377575en
dc.identifier.urihttps://hdl.handle.net/10919/123837en
dc.identifier.volume15en
dc.language.isoenen
dc.publisherAmerican Society for Microbiologyen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/39377575en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjecthepatitis E virus (HEV)en
dc.subjectHEV-3en
dc.subjectzoonotic infectionen
dc.subjecthypervariable region (HVR)en
dc.subjectphosphorylationen
dc.subjectmutagenesisen
dc.subjectviral replicationen
dc.subjecthost tropismen
dc.subject.meshAnimalsen
dc.subject.meshHumansen
dc.subject.meshHepatitis E virusen
dc.subject.meshZoonosesen
dc.subject.meshHepatitis Een
dc.subject.meshSerineen
dc.subject.meshVirus Replicationen
dc.subject.meshPhosphorylationen
dc.subject.meshGenotypeen
dc.titlePhosphorylation of Ser711 Residue in the Hypervariable Region of Zoonotic Genotype 3 Hepatitis E Virus is Important for Virus Replicationen
dc.title.serialmBioen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherEarly Accessen
dc.type.otherJournalen
pubs.finish-date2024-06-28en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Veterinary Medicineen
pubs.organisational-groupVirginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-groupVirginia Tech/University Distinguished Professorsen
pubs.organisational-groupVirginia Tech/Faculty of Health Sciencesen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/Veterinary Medicine/CVM T&R Facultyen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Internal Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Internal Medicine/Secondary Appointment- Internal Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Internal Medicine/Internal Med-Subgroupen
pubs.start-date2024-06-24en

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