{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T23:21:25Z","timestamp":1773098485800,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Natural Science Foundation of Chongqing","award":["CSTB2022NSCQ-MSX0311"],"award-info":[{"award-number":["CSTB2022NSCQ-MSX0311"]}]},{"name":"the Natural Science Foundation of Chongqing","award":["cstc2020jcyj-msxmX0446"],"award-info":[{"award-number":["cstc2020jcyj-msxmX0446"]}]},{"name":"the Natural Science Foundation of Chongqing","award":["CSTB2022NSCQ-MSX0311"],"award-info":[{"award-number":["CSTB2022NSCQ-MSX0311"]}]},{"name":"the Natural Science Foundation of Chongqing","award":["cstc2020jcyj-msxmX0446"],"award-info":[{"award-number":["cstc2020jcyj-msxmX0446"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Hepatitis E (Hepatitis E, HE) is an acute and chronic infectious hepatitis caused by hepatitis E virus (Hepatitis E Virus, HEV) infection, which is responsible for most acute hepatitis in the world and is a significant public health problem. The pathogen, HEV, has three Open Reading Frames (ORFs) ORF1, ORF2, and ORF3, each of which has a different function. Most of the current research is focused on ORF1 and ORF2, while the research on ORF3 is still relatively small. To provide more ideas for the study of HEV pathogenesis and the prevention and treatment of HE, this paper reviews the effects of ORF3 on the ERK pathway, growth factors, immune response, and virus release.<\/jats:p>","DOI":"10.3390\/microorganisms12071405","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T11:30:55Z","timestamp":1720697455000},"page":"1405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Multiple Functions of Hepatitis E Virus ORF3"],"prefix":"10.3390","volume":"12","author":[{"given":"Fengyuan","family":"Jiao","sequence":"first","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Ministry of Agriculture and Rural Affairs Key Laboratory of Crop Genitic Resources and Germplasm Innovation in Karst Region, Institute of Animal Husbandry and Veterinary Medicine of Guizhou Academy of Agricultural Science, Guiyang 550005, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gengxu","family":"Zhou","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi","family":"Meng","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingjie","family":"Wang","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengping","family":"Wu","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jixiang","family":"Li","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4697-8509","authenticated-orcid":false,"given":"Liting","family":"Cao","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang Street 573, Changchun 130102, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yichen","family":"Luo","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanwei","family":"Jiao","sequence":"additional","affiliation":[{"name":"The College of Veterinary Medicine, Southwest University, Chongqing 402460, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17086","DOI":"10.1038\/nrdp.2017.86","article-title":"Hepatitis E Virus Infection","volume":"3","author":"Kamar","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/S1473-3099(08)70255-X","article-title":"Hepatitis E: An Emerging Infection in Developed Countries","volume":"8","author":"Dalton","year":"2008","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.virusres.2011.01.015","article-title":"Hepatitis E Virus Cell Culture Models","volume":"161","author":"Okamoto","year":"2011","journal-title":"Virus Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e00585-21","DOI":"10.1128\/JVI.00585-21","article-title":"The Viral ORF3 Protein Is Required for Hepatitis E Virus Apical Release and Efficient Growth in Polarized Hepatocytes and Humanized Mice","volume":"95","author":"Sari","year":"2021","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Osamudiamen, F.T., Akanbi, O.A., Zander, S., Oluwayelu, D.O., Bock, C.-T., and Klink, P. (2021). Identification of a Putative Novel Genotype of Avian Hepatitis E Virus from Apparently Healthy Chickens in Southwestern Nigeria. Viruses, 13.","DOI":"10.3390\/v13060954"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Wang, Y. (2016). Hepatitis E Virus, Springer. Advances in Experimental Medicine and Biology.","DOI":"10.1007\/978-94-024-0942-0"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pezzoni, G., Stercoli, L., Pegoiani, E., and Brocchi, E. (2021). Antigenic Characterization of ORF2 and ORF3 Proteins of Hepatitis E Virus (HEV). Viruses, 13.","DOI":"10.3390\/v13071385"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.jhep.2023.03.024","article-title":"The Pressing Need for a Global HEV Vaccine","volume":"79","author":"Peron","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1128\/IAI.70.6.3004-3011.2002","article-title":"Identification of a Quorum-Sensing Signal Molecule in the Facultative Intracellular Pathogen Brucella melitensis","volume":"70","author":"Taminiau","year":"2002","journal-title":"Infect. Immun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/jvh.12445","article-title":"Hepatitis E: An Emerging Global Disease\u2014From Discovery towards Control and Cure","volume":"23","author":"Khuroo","year":"2016","journal-title":"J. Viral. Hepat."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"LeDesma, R., Nimgaonkar, I., and Ploss, A. (2019). Hepatitis E Virus Replication. Viruses, 11.","DOI":"10.3390\/v11080719"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2401","DOI":"10.1002\/rmv.2401","article-title":"Hepatitis E Virus (HEV) Open Reading Frame 2: Role in Pathogenesis and Diagnosis in HEV Infections","volume":"32","author":"Sayed","year":"2022","journal-title":"Rev. Med. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.3748\/wjg.v27.i20.2458","article-title":"Open Reading Frame 3 Protein of Hepatitis E Virus: Multi-Function Protein with Endless Potential","volume":"27","author":"Yang","year":"2021","journal-title":"WJG"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1073\/pnas.1614955114","article-title":"Hepatitis E Virus ORF3 Is a Functional Ion Channel Required for Release of Infectious Particles","volume":"114","author":"Ding","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7100","DOI":"10.1128\/JVI.00403-08","article-title":"The Hepatitis E Virus ORF3 Protein Modulates Epidermal Growth Factor Receptor Trafficking, STAT3 Translocation, and the Acute-Phase Response","volume":"82","author":"Chandra","year":"2008","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1099\/vir.0.066910-0","article-title":"Hepatitis E Virus Egress Depends on the Exosomal Pathway, with Secretory Exosomes Derived from Multivesicular Bodies","volume":"95","author":"Nagashima","year":"2014","journal-title":"J. Gen. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6375","DOI":"10.1128\/JVI.02571-08","article-title":"The Hepatitis E Virus Open Reading Frame 3 Product Interacts with Microtubules and Interferes with Their Dynamics","volume":"83","author":"Kannan","year":"2009","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9045","DOI":"10.1128\/jvi.71.12.9045-9053.1997","article-title":"The ORF3 Protein of Hepatitis E Virus Is a Phosphoprotein That Associates with the Cytoskeleton","volume":"71","author":"Zafrullah","year":"1997","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"28345","DOI":"10.1074\/jbc.M400457200","article-title":"The Hepatitis E Virus Open Reading Frame 3 Protein Activates ERK through Binding and Inhibition of the MAPK Phosphatase","volume":"279","author":"Korkaya","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ventura, C., Banerjee, A., Zacharopoulou, M., Itzhaki, L.S., and Bahar, I. (2024). Tandem-Repeat Proteins Conformational Mechanics Are Optimized to Facilitate Functional Interactions and Complexations. Curr. Opin. Struct. Biol., 84.","DOI":"10.1016\/j.sbi.2023.102744"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"42389","DOI":"10.1074\/jbc.M101546200","article-title":"The ORF3 Protein of Hepatitis E Virus Binds to Src Homology 3 Domains and Activates MAPK","volume":"276","author":"Korkaya","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/978-94-024-0942-0_2","article-title":"Characteristics and Functions of HEV Proteins","volume":"948","author":"Zhou","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/rmv.522","article-title":"Hepatitis E Virus","volume":"17","author":"Panda","year":"2007","journal-title":"Rev. Med. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gouttenoire, J., Poll\u00e1n, A., Abrami, L., Oechslin, N., Mauron, J., Matter, M., Oppliger, J., Szkolnicka, D., Dao Thi, V.L., and van der Goot, F.G. (2018). Palmitoylation Mediates Membrane Association of Hepatitis E Virus ORF3 Protein and Is Required for Infectious Particle Secretion. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007471"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1111\/febs.12263","article-title":"What Does S-Palmitoylation Do to Membrane Proteins?","volume":"280","author":"Blaskovic","year":"2013","journal-title":"FEBS J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"21124","DOI":"10.1074\/jbc.M701696200","article-title":"The Hepatitis E Virus Orf3 Protein Protects Cells from Mitochondrial Depolarization and Death","volume":"282","author":"Moin","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3857","DOI":"10.1128\/JVI.01994-09","article-title":"The ORF3 Protein of Hepatitis E Virus Delays Degradation of Activated Growth Factor Receptors by Interacting with CIN85 and Blocking Formation of the Cbl-CIN85 Complex","volume":"84","author":"Chandra","year":"2010","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.1093\/emboj\/cdf351","article-title":"Cytoplasmic Transport of Stat3 by Receptor-Mediated Endocytosis","volume":"21","author":"Bild","year":"2002","journal-title":"EMBO J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"27597","DOI":"10.1038\/srep27597","article-title":"The ORF3 Protein of Genotype 1 Hepatitis E Virus Suppresses TLR3-Induced NF-\u03baB Signaling via TRADD and RIP1","volume":"6","author":"He","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3214","DOI":"10.1038\/sj.onc.1210413","article-title":"Ubiquitin-Mediated Activation of TAK1 and IKK","volume":"26","author":"Adhikari","year":"2007","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8135","DOI":"10.1074\/jbc.M509568200","article-title":"Enhanced A1 Microglobulin Secretion from Hepatitis E Virus ORF3-Expressing Human Hepatoma Cells Is Mediated by the Tumor Susceptibility Gene 101*","volume":"281","author":"Surjit","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1099\/vir.0.025791-0","article-title":"A PSAP Motif in the ORF3 Protein of Hepatitis E Virus Is Necessary for Virion Release from Infected Cells","volume":"92","author":"Nagashima","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1477-5956-9-5","article-title":"Plasma Peptidome Profiling of Acute Hepatitis E Patients by MALDI-TOF\/TOF","volume":"9","author":"Taneja","year":"2011","journal-title":"Proteome Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1021\/bi7016552","article-title":"The ORF3 Protein of Hepatitis E Virus Interacts with Hemopexin by Means of Its 26 Amino Acid N-Terminal Hydrophobic Domain II","volume":"47","author":"Ratra","year":"2008","journal-title":"Biochemistry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6680","DOI":"10.1128\/JVI.79.11.6680-6689.2005","article-title":"The Open Reading Frame 3 Gene of Hepatitis E Virus Contains a Cis-Reactive Element and Encodes a Protein Required for Infection of Macaques","volume":"79","author":"Graff","year":"2005","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"22759","DOI":"10.1074\/jbc.M200185200","article-title":"The Phosphorylated Form of the ORF3 Protein of Hepatitis E Virus Interacts with Its Non-Glycosylated Form of the Major Capsid Protein, ORF2*","volume":"277","author":"Tyagi","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Glitscher, M., and Hildt, E. (2021). Hepatitis E Virus Egress and beyond\u2014The Manifold Roles of the Viral ORF3 Protein. Cell. Microbiol., 23.","DOI":"10.1111\/cmi.13379"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"197868","DOI":"10.1016\/j.virusres.2020.197868","article-title":"Multivesicular Body Sorting and the Exosomal Pathway Are Required for the Release of Rat Hepatitis E Virus from Infected Cells","volume":"278","author":"Primadharsini","year":"2020","journal-title":"Virus Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12986","DOI":"10.1073\/pnas.0903699106","article-title":"Biological and Immunological Characteristics of Hepatitis E Virus-like Particles Based on the Crystal Structure","volume":"106","author":"Yamashita","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10457","DOI":"10.1128\/JVI.00892-06","article-title":"ORF3 Protein of Hepatitis E Virus Is Not Required for Replication, Virion Assembly, or Infection of Hepatoma Cells in Vitro","volume":"80","author":"Emerson","year":"2006","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1016\/j.csbj.2021.03.038","article-title":"Structural and Molecular Biology of Hepatitis E Virus","volume":"19","author":"Wang","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Xu, K., Guo, S., Zhao, T., Zhu, H., Jiao, H., Shi, Q., Pang, F., Li, Y., Li, G., and Peng, D. (2016). Transcriptome Analysis of HepG2 Cells Expressing ORF3 from Swine Hepatitis E Virus to Determine the Effects of ORF3 on Host Cells. BioMed. Res. Int., 2016.","DOI":"10.1155\/2016\/1648030"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Qi, Y., Zhang, F., Zhang, L., Harrison, T.J., Huang, W., Zhao, C., Kong, W., Jiang, C., and Wang, Y. (2015). Hepatitis E Virus Produced from Cell Culture Has a Lipid Envelope. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132503"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1128\/JCM.02002-09","article-title":"Hepatitis E Virus (HEV) Strains in Serum Samples Can Replicate Efficiently in Cultured Cells Despite the Coexistence of HEV Antibodies: Characterization of HEV Virions in Blood Circulation","volume":"48","author":"Takahashi","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1002\/jmv.25400","article-title":"HEV ORF3 downregulatesCD14 and CD64 to Impair Macrophages Phagocytosis through Inhibiting JAK\/STAT Pathway","volume":"91","author":"Lei","year":"2019","journal-title":"J. Med. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8585","DOI":"10.1038\/s41598-018-26975-4","article-title":"HEV ORF3 Downregulates TLR7 to Inhibit the Generation of Type I Interferon via Impairment of Multiple Signaling Pathways","volume":"8","author":"Lei","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Mazalovska, M., and Kouokam, J.C. (2020). Progress in the Production of Virus-Like Particles for Vaccination against Hepatitis E Virus. Viruses, 12.","DOI":"10.3390\/v12080826"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Yan, H., Chi, Z., Zhao, H., Zhang, Y., Zhang, Y., Wang, Y., Chang, S., and Zhao, P. (2022). Application of ORF3 Subunit Vaccine for Avian Hepatitis E Virus. Vet. Sci., 9.","DOI":"10.3390\/vetsci9120676"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e29691","DOI":"10.1002\/jmv.29691","article-title":"Multifunctional ORF3 Protein of Hepatitis E Virus","volume":"96","author":"Li","year":"2024","journal-title":"J. Med. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.jhep.2023.12.016","article-title":"Efficient Formation and Maintenance of Humoral and CD4 T-Cell Immunity Targeting the Viral Capsid in Acute-Resolving Hepatitis E Infection","volume":"80","author":"Csernalabics","year":"2024","journal-title":"J. Hepatol."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/7\/1405\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:15:08Z","timestamp":1760109308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/7\/1405"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,11]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["microorganisms12071405"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms12071405","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,11]]}}}