{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:45:01Z","timestamp":1787737501191,"version":"build-2784847793"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,12,26]],"date-time":"2018-12-26T00:00:00Z","timestamp":1545782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81471953"],"award-info":[{"award-number":["81471953"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81672036"],"award-info":[{"award-number":["81672036"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004739","name":"Youth Innovation Promotion Association of the Chinese Academy of Sciences","doi-asserted-by":"publisher","award":["2016302"],"award-info":[{"award-number":["2016302"]}],"id":[{"id":"10.13039\/501100004739","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Enterovirus A71 (EVA71) is a human enterovirus belonging to the Picornaviridae family and mostly causes hand-foot-and-mouth disease in infants. Viperin is an important interferon-stimulated gene with a broad antiviral activity against various viruses. However, the effect of viperin on human enteroviruses and the interaction mechanism between EVA71 and viperin remains elusive. Here, we confirmed the EVA71-induced expression of viperin in a mouse model and cell lines and showed that viperin upregulation by EVA71 infection occurred on both the mRNA and protein level. Viperin knockdown and overexpression in EVA71-infected cells indicated that this protein can markedly inhibit EVA71 infection. Interestingly, immunofluorescent confocal microscopy and co-immunoprecipitation assays indicated that viperin interacts and colocalizes with the EVA71 protein 2C in the endoplasmic reticulum. Furthermore, amino acids 50\u201360 in the N-terminal domain of viperin were the key residues responsible for viperin interaction with 2C. More importantly, the N-terminal domain of viperin was found responsible for inhibiting EVA71 replication. Our findings can potentially aid future research on the prevention and treatment of nervous system damage caused by EVA71 and may provide a potential target for antiviral therapy.<\/jats:p>","DOI":"10.3390\/v11010013","type":"journal-article","created":{"date-parts":[[2018,12,26]],"date-time":"2018-12-26T11:31:21Z","timestamp":1545823881000},"page":"13","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Viperin Inhibits Enterovirus A71 Replication by Interacting with Viral 2C Protein"],"prefix":"10.3390","volume":"11","author":[{"given":"Chunyu","family":"Wei","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caishang","family":"Zheng","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhong","family":"Sun","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Luo","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianliang","family":"Ke","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4117-9364","authenticated-orcid":false,"given":"Zhenhua","family":"Zheng","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanzhong","family":"Wang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2222\/jsv.56.1","article-title":"Innate immune recognition of viral infection","volume":"56","author":"Uematsu","year":"2006","journal-title":"Uirusu"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1146\/annurev-immunol-032713-120231","article-title":"Interferon-stimulated genes: A complex web of host defenses","volume":"32","author":"Schneider","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1128\/JVI.01531-10","article-title":"The IFITM proteins inhibit HIV-1 infection","volume":"85","author":"Lu","year":"2011","journal-title":"J. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nri3344","article-title":"The broad-spectrum antiviral functions of IFIT and IFITM proteins","volume":"13","author":"Diamond","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1016\/j.jmb.2013.10.019","article-title":"The role of viperin in the innate antiviral response","volume":"426","author":"Helbig","year":"2014","journal-title":"J. Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/S1473-3099(10)70194-8","article-title":"Virology, epidemiology, pathogenesis, and control of enterovirus 71","volume":"10","author":"Solomon","year":"2010","journal-title":"Lancet Infect. Dis."},{"key":"ref_7","unstructured":"Pallansch, M., and Roos, R. (2001). Fields Virology, Lippicott Williams & Wilkins."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Xia, H., Wang, P., Wang, G.-C., Yang, J., Sun, X., Wu, W., Qiu, Y., Shu, T., Zhao, X., and Yin, L. (2015). Human enterovirus nonstructural protein 2CATPase functions as both an RNA helicase and ATP-independent RNA chaperone. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005067"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Liu, Y., Wang, C., Mueller, S., Paul, A.V., Wimmer, E., and Jiang, P. (2010). Direct interaction between two viral proteins, the nonstructural protein 2CATPase and the capsid protein VP3, is required for enterovirus morphogenesis. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001066"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5888","DOI":"10.1074\/jbc.M611145200","article-title":"Reticulon 3 binds the 2C protein of enterovirus 71 and is required for viral replication","volume":"282","author":"Tang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.4049\/jimmunol.1100285","article-title":"Enterovirus 71 2C protein inhibits TNF-\u03b1-mediated activation of NF-\u03baB by suppressing I\u03baB kinase \u03b2 phosphorylation","volume":"187","author":"Zheng","year":"2011","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1089\/jir.2010.0127","article-title":"The interferon inducible gene: Viperin","volume":"31","author":"Fitzgerald","year":"2011","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.chom.2007.06.009","article-title":"The interferon-inducible protein viperin inhibits influenza virus release by perturbing lipid rafts","volume":"2","author":"Wang","year":"2007","journal-title":"Cell Host Microbe"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1182\/blood-2012-01-407395","article-title":"HIV-1 infection of human macrophages directly induces viperin which inhibits viral production","volume":"120","author":"Nasr","year":"2012","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Helbig, K.J., Carr, J.M., Calvert, J.K., Wati, S., Clarke, J.N., Eyre, N.S., Narayana, S.K., Fiches, G.N., McCartney, E.M., and Beard, M.R. (2013). Viperin is induced following dengue virus type-2 (DENV-2) infection and has anti-viral actions requiring the C-terminal end of viperin. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002178"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1099\/vir.0.033860-0","article-title":"Viperin inhibits hepatitis C virus replication by interfering with binding of NS5A to host protein hVAP-33","volume":"93","author":"Wang","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15125","DOI":"10.1073\/pnas.011593298","article-title":"Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus","volume":"98","author":"Chin","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1126\/science.1202007","article-title":"Human cytomegalovirus directly induces the antiviral protein viperin to enhance infectivity","volume":"332","author":"Seo","year":"2011","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11557","DOI":"10.1128\/JVI.05519-11","article-title":"The interferon-inducible gene viperin restricts West Nile virus pathogenesis","volume":"85","author":"Szretter","year":"2011","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11246","DOI":"10.1128\/JVI.01282-07","article-title":"Identification and characterization of interferon-induced proteins that inhibit alphavirus replication","volume":"81","author":"Zhang","year":"2007","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4735","DOI":"10.4049\/jimmunol.177.7.4735","article-title":"TLR3 ligation activates an antiviral response in human fetal astrocytes: A role for viperin\/cig5","volume":"177","author":"Rivieccio","year":"2006","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1172\/JCI63120","article-title":"Viperin restricts chikungunya virus replication and pathology","volume":"122","author":"Teng","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Panayiotou, C., Lindqvist, R., Kurhade, C., Vonderstein, K., Pasto, J., Edlund, K., Upadhyay, A.S., and Overby, A.K. (2018). Viperin Restricts Zika Virus and Tick-Borne Encephalitis Virus Replication by Targeting NS3 for Proteasomal Degradation. J. Virol., 92.","DOI":"10.1128\/JVI.00501-18"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e01751-17","DOI":"10.1128\/JVI.01751-17","article-title":"Viperin targets flavivirus virulence by inducing assembly of non-infectious capsid particles","volume":"92","author":"Vonderstein","year":"2018","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/s41586-018-0238-4","article-title":"A naturally occurring antiviral ribonucleotide encoded by the human genome","volume":"558","author":"Gizzi","year":"2018","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10472","DOI":"10.1128\/JVI.01756-16","article-title":"SUMO Modification Stabilizes Enterovirus 71 Polymerase 3D To Facilitate Viral Replication","volume":"90","author":"Liu","year":"2016","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.antiviral.2016.11.008","article-title":"Clinically isolated enterovirus A71 subgenogroup C4 strain with lethal pathogenicity in 14-day-old mice and the application as an EV-A71 mouse infection model","volume":"137","author":"Xu","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4705","DOI":"10.1074\/jbc.M807261200","article-title":"The N-terminal amphipathic alpha-helix of viperin mediates localization to the cytosolic face of the endoplasmic reticulum and inhibits protein secretion","volume":"284","author":"Hinson","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8962","DOI":"10.1128\/jvi.71.12.8962-8972.1997","article-title":"Poliovirus 2C protein determinants of membrane binding and rearrangements in mammalian cells","volume":"71","author":"Teterina","year":"1997","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/j.1600-065X.2008.00737.x","article-title":"Innate immunity to virus infection","volume":"227","author":"Takeuchi","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/ni1303","article-title":"Innate immune recognition of viral infection","volume":"7","author":"Kawai","year":"2006","journal-title":"Nat. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3263","DOI":"10.1099\/vir.0.81195-0","article-title":"Type I interferons protect mice against enterovirus 71 infection","volume":"86","author":"Liu","year":"2005","journal-title":"J. Gen. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3851\/IMP1720","article-title":"Potent inhibition of human enterovirus 71 replication by type I interferon subtypes","volume":"16","author":"Yi","year":"2011","journal-title":"Antivir. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.chom.2011.11.004","article-title":"Viperin: A multifunctional, interferon-inducible protein that regulates virus replication","volume":"10","author":"Seo","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e01914","DOI":"10.1128\/JVI.01914-17","article-title":"RSAD2 and AIM2 Modulate Coxsackievirus A16 and Enterovirus A71 Replication in Neuronal Cells in Different Ways That May Be Associated with Their 5\u2032 Nontranslated Regions","volume":"92","author":"Yogarajah","year":"2018","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.micinf.2011.11.015","article-title":"Viperin, a key player in the antiviral response","volume":"14","author":"Mattijssen","year":"2012","journal-title":"Microbes Infect."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5179","DOI":"10.4049\/jimmunol.0902264","article-title":"IFN regulatory factor-1 bypasses IFN-mediated antiviral effects through viperin gene induction","volume":"184","author":"Stirnweiss","year":"2010","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1128\/JVI.80.2.1032-1037.2006","article-title":"Interferon regulatory factor 3 is necessary for induction of antiviral genes during human cytomegalovirus infection","volume":"80","author":"DeFilippis","year":"2006","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5532","DOI":"10.1128\/JVI.76.11.5532-5539.2002","article-title":"Transcriptional profiling of interferon regulatory factor 3 target genes: Direct involvement in the regulation of interferon-stimulated genes","volume":"76","author":"Grandvaux","year":"2002","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1099\/vir.0.040824-0","article-title":"In vivo and in vitro studies on the antiviral activities of viperin against influenza H1N1 virus infection","volume":"93","author":"Tan","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1111\/cmi.12241","article-title":"Viperin is an iron-sulfur protein that inhibits genome synthesis of tick-borne encephalitis virus via radical SAM domain activity","volume":"16","author":"Upadhyay","year":"2014","journal-title":"Cell. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6806","DOI":"10.1073\/pnas.1705402114","article-title":"Structural studies of viperin, an antiviral radical SAM enzyme","volume":"114","author":"Fenwick","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"26806","DOI":"10.1074\/jbc.M116.751040","article-title":"Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity?","volume":"291","author":"Makins","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.febslet.2010.02.041","article-title":"The antiviral protein viperin is a radical SAM enzyme","volume":"584","author":"Duschene","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"11548","DOI":"10.1128\/JVI.01773-12","article-title":"Viperin, MTAP44, and protein kinase R contribute to the interferon-induced inhibition of Bunyamwera Orthobunyavirus replication","volume":"86","author":"Elliott","year":"2012","journal-title":"J. Virol."},{"key":"ref_46","first-page":"363","article-title":"Modification of intracellular membrane structures for virus replication. Nature reviews","volume":"6","author":"Miller","year":"2008","journal-title":"Microbiology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e00166-11","DOI":"10.1128\/mBio.00166-11","article-title":"The Transformation of Enterovirus Replication Structures: A Three-Dimensional Study of Single- and Double-Membrane Compartments","volume":"2","author":"Limpens","year":"2011","journal-title":"mBio"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1164\/rccm.200805-670OC","article-title":"Gene expression profiles during in vivo human rhinovirus infection: Insights into the host response","volume":"178","author":"Proud","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/1\/13\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:36:10Z","timestamp":1760196970000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/1\/13"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,26]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,1]]}},"alternative-id":["v11010013"],"URL":"https:\/\/doi.org\/10.3390\/v11010013","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,26]]}}}