{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T07:37:21Z","timestamp":1789198641395,"version":"build-2803163510"},"reference-count":67,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2015,4,22]],"date-time":"2015-04-22T00:00:00Z","timestamp":1429660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-GM057454"],"award-info":[{"award-number":["R01-GM057454"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Alphaviruses such as chikungunya virus (CHIKV) and Semliki Forest virus (SFV) are small enveloped RNA viruses that bud from the plasma membrane. Tetherin\/BST2 is an interferon-induced host membrane protein that inhibits the release of many enveloped viruses via direct tethering of budded particles to the cell surface. Alphaviruses have  highly organized structures and exclude host membrane proteins from the site of budding, suggesting that their release might be insensitive to tetherin inhibition. Here, we demonstrated that exogenously-expressed tetherin efficiently inhibited the release of SFV and CHIKV particles from host cells without affecting virus entry and infection. Alphavirus release was also inhibited by the endogenous levels of tetherin in HeLa cells. While rubella virus (RuV) and dengue virus (DENV) have structural similarities to alphaviruses, tetherin inhibited the release of RuV but not DENV. We found that two recently identified tetherin isoforms differing in length at the N-terminus exhibited distinct capabilities in restricting alphavirus release. SFV exit was efficiently inhibited by the long isoform but not the short isoform of tetherin, while both isoforms inhibited vesicular stomatitis virus exit. Thus, in spite of the organized structure of the virus particle, tetherin specifically blocks alphavirus release and shows an interesting isoform requirement.<\/jats:p>","DOI":"10.3390\/v7042147","type":"journal-article","created":{"date-parts":[[2015,4,22]],"date-time":"2015-04-22T12:14:23Z","timestamp":1429704863000},"page":"2147-2167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["BST2\/Tetherin Inhibition of Alphavirus Exit"],"prefix":"10.3390","volume":"7","author":[{"given":"Yaw","family":"Ooi","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx,  NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Dub\u00e9","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx,  NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7395-4791","authenticated-orcid":false,"given":"Margaret","family":"Kielian","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx,  NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,4,22]]},"reference":[{"key":"ref_1","first-page":"629","article-title":"Togaviridae","volume":"Volume 1","author":"Knipe","year":"2013","journal-title":"Fields Virology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.antiviral.2012.04.002","article-title":"Alphaviruses: Population genetics and determinants of emergence","volume":"94","author":"Weaver","year":"2012","journal-title":"Antivir. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"D80","DOI":"10.1016\/j.vaccine.2009.07.095","article-title":"Vaccines for venezuelan equine encephalitis","volume":"27","author":"Paessler","year":"2009","journal-title":"Vaccine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2217\/fmb.09.59","article-title":"A structural and functional perspective of alphavirus replication and assembly","volume":"4","author":"Jose","year":"2009","journal-title":"Future Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.str.2005.07.025","article-title":"Mapping the structure and function of the e1 and e2 glycoproteins in alphaviruses","volume":"14","author":"Mukhopadhyay","year":"2006","journal-title":"Structure"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nature09555","article-title":"Glycoprotein organization of chikungunya virus particles revealed by x-ray crystallography","volume":"468","author":"Voss","year":"2010","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/nature09546","article-title":"Structural changes of envelope proteins during alphavirus fusion","volume":"468","author":"Li","year":"2010","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"796","DOI":"10.3390\/v2040796","article-title":"Alphavirus entry and membrane fusion","volume":"2","author":"Kielian","year":"2010","journal-title":"Viruses"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1146\/annurev-biochem-060208-104626","article-title":"Virus entry by endocytosis","volume":"79","author":"Mercer","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1146\/annurev-virology-031413-085521","article-title":"Mechanisms of virus membrane fusion proteins","volume":"1","author":"Kielian","year":"2014","journal-title":"Annu. Rev. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6922","DOI":"10.1128\/JVI.00592-14","article-title":"Imaging the alphavirus exit pathway","volume":"88","author":"Martinez","year":"2014","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"463","DOI":"10.3109\/10409238.2010.502516","article-title":"The ESCRT complexes","volume":"45","author":"Hurley","year":"2010","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13631","DOI":"10.1128\/JVI.01688-07","article-title":"Ubiquitin depletion and dominant-negative vps4 inhibit rhabdovirus budding without affecting alphavirus budding","volume":"81","author":"Taylor","year":"2007","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13688","DOI":"10.1073\/pnas.1101684108","article-title":"In vivo expression profile of the antiviral restriction factor and tumor-targeting antigen cd317\/bst-2\/hm1.24\/tetherin in humans","volume":"108","author":"Erikson","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/nature06553","article-title":"Tetherin inhibits retrovirus release and is antagonized by HIV-1 vpu","volume":"451","author":"Neil","year":"2008","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11966","DOI":"10.1128\/JVI.01515-09","article-title":"Antagonism to and intracellular sequestration of human tetherin by the human immunodeficiency virus type 2 envelope glycoprotein","volume":"83","author":"Neil","year":"2009","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9672","DOI":"10.1128\/JVI.00597-09","article-title":"Molecular mechanism of bst2\/tetherin downregulation by k5\/mir2 of kaposi's sarcoma-associated herpesvirus","volume":"83","author":"Mansouri","year":"2009","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2886","DOI":"10.1073\/pnas.0811014106","article-title":"Tetherin-mediated restriction of filovirus budding is antagonized by the ebola glycoprotein","volume":"106","author":"Kaletsky","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12646","DOI":"10.1128\/JVI.01328-10","article-title":"Interferon-induced cell membrane proteins, ifitm3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms","volume":"84","author":"Weidner","year":"2010","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3390\/v3050520","article-title":"Antiviral inhibition of enveloped virus release by tetherin\/bst-2: Action and counteraction","volume":"3","author":"Willey","year":"2011","journal-title":"Viruses"},{"key":"ref_21","first-page":"67","article-title":"The antiviral activities of tetherin","volume":"371","author":"Neil","year":"2013","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.molimm.2012.11.008","article-title":"Bst-2\/tetherin: Structural biology, viral antagonism, and immunobiology of a potent host antiviral factor","volume":"54","author":"Swiecki","year":"2013","journal-title":"Mol. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.chom.2010.03.005","article-title":"Structural basis of HIV-1 tethering to membranes by the bst-2\/tetherin ectodomain","volume":"7","author":"Hinz","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1034\/j.1600-0854.2003.00129.x","article-title":"Bst-2\/hm1.24 is a raft-associated apical membrane protein with an unusual topology","volume":"4","author":"Kupzig","year":"2003","journal-title":"Traffic"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1242\/jcs.003343","article-title":"Clathrin-mediated endocytosis of a lipid-raft-associated protein is mediated through a dual tyrosine motif","volume":"120","author":"Rollason","year":"2007","journal-title":"J. Cell Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15927","DOI":"10.1074\/jbc.M109.005124","article-title":"Hm1.24 is internalized from lipid rafts by clathrin-mediated endocytosis through interaction with alpha-adaptin","volume":"284","author":"Masuyama","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1003483","DOI":"10.1371\/journal.ppat.1003483","article-title":"Mechanism of HIV-1 virion entrapment by tetherin","volume":"9","author":"Venkatesh","year":"2013","journal-title":"PLOS Pathog."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e1000700","DOI":"10.1371\/journal.ppat.1000700","article-title":"Bca2\/rabring7 promotes tetherin-dependent HIV-1 restriction","volume":"5","author":"Miyakawa","year":"2009","journal-title":"PLOS Pathog."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1111\/j.1462-5822.2007.01101.x","article-title":"HIV-1 vpu inhibits accumulation of the envelope glycoprotein within clathrin-coated, gag-containing endosomes","volume":"10","author":"Guatelli","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e1002931","DOI":"10.1371\/journal.ppat.1002931","article-title":"Identification of alternatively translated tetherin isoforms with differing antiviral and signaling activities","volume":"8","author":"Cocka","year":"2012","journal-title":"PLOS Pathog."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1128\/JVI.02272-12","article-title":"Stimulation of nf-kappab activity by the HIV restriction factor bst2","volume":"87","author":"Tokarev","year":"2013","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.chom.2012.10.007","article-title":"Innate sensing of HIV-1 assembly by tetherin induces nfkappab-dependent proinflammatory responses","volume":"12","author":"Galao","year":"2012","journal-title":"Cell Host Microbe"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1128\/JVI.72.5.4281-4287.1998","article-title":"Fus-1, a ph-shift mutant of semliki forest virus, acts by altering spike subunit interactions via a mutation in the e2 subunit","volume":"72","author":"Kielian","year":"1998","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e8325","DOI":"10.1371\/journal.pone.0008325","article-title":"Efficient assembly and secretion of recombinant subviral particles of the four dengue serotypes using native prm and e proteins","volume":"4","author":"Wang","year":"2009","journal-title":"PLOS ONE"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1073\/pnas.0813223106","article-title":"Vpu enhances HIV-1 virus release in the absence of bst-2 cell surface down-modulation and intracellular depletion","volume":"106","author":"Miyagi","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1083\/jcb.140.1.91","article-title":"A single point mutation controls the cholesterol dependence of semliki forest virus entry and exit","volume":"140","author":"Vashishtha","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0042-6822(82)90125-8","article-title":"The interaction of antibody with the major surface glycoprotein of vesicular stomatitis virus. I. Analysis of neutralizing epitopes with monoclonal antibodies","volume":"121","author":"Lefrancois","year":"1982","journal-title":"Virology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13975","DOI":"10.1128\/JVI.78.24.13975-13986.2004","article-title":"Localization and characterization of flavivirus envelope glycoprotein cross-reactive epitopes","volume":"78","author":"Crill","year":"2004","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1083\/jcb.112.4.615","article-title":"Cholesterol is required for infection by semliki forest virus","volume":"112","author":"Phalen","year":"1991","journal-title":"J. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1083\/jcb.98.1.139","article-title":"Membrane fusion mutants of semliki forest virus","volume":"98","author":"Kielian","year":"1984","journal-title":"J. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e1001157","DOI":"10.1371\/journal.ppat.1001157","article-title":"In vitro and in vivo studies identify important features of dengue virus pr-E protein interactions","volume":"6","author":"Zheng","year":"2010","journal-title":"PLOS Pathog."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1128\/mr.58.3.491-562.1994","article-title":"The alphaviruses: Gene expression, replication, and evolution","volume":"58","author":"Strauss","year":"1994","journal-title":"Microbiol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/nbt1210-1248","article-title":"Towards a knowledge-based human protein atlas","volume":"28","author":"Uhlen","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.chom.2007.08.001","article-title":"An interferon-alpha-induced tethering mechanism inhibits HIV-1 and ebola virus particle release but is counteracted by the HIV-1 vpu protein","volume":"2","author":"Neil","year":"2007","journal-title":"Cell Host Microbe"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e1002332","DOI":"10.1371\/journal.ppat.1002332","article-title":"Bst2\/tetherin enhances entry of human cytomegalovirus","volume":"7","author":"Viswanathan","year":"2011","journal-title":"PLOS Pathog."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1099\/0022-1317-58-1-47","article-title":"Inhibition of semliki forest virus penetration by lysosomotropic weak bases","volume":"58","author":"Helenius","year":"1982","journal-title":"J. Gen. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nature11741","article-title":"Functional and evolutionary insight from the crystal structure of rubella virus protein e1","volume":"493","author":"DuBois","year":"2013","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/S0092-8674(02)00660-8","article-title":"Structure of dengue virus: Implications for flavivirus organization, maturation, and fusion","volume":"108","author":"Kuhn","year":"2002","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0042-6822(03)00384-2","article-title":"Structural maturation of rubella virus in the golgi complex","volume":"312","author":"Risco","year":"2003","journal-title":"Virology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrmicro1067","article-title":"A structural perspective of the flavivirus life cycle","volume":"3","author":"Mukhopadhyay","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1006\/viro.1994.1379","article-title":"Assembly of rubella virus structural proteins into virus-like particles in transfected cells","volume":"202","author":"Hobman","year":"1994","journal-title":"Virology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e51033","DOI":"10.1371\/journal.pone.0051033","article-title":"Bst2\/tetherin inhibits dengue virus release from human hepatoma cells","volume":"7","author":"Pan","year":"2012","journal-title":"PLOS ONE"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8147","DOI":"10.1128\/JVI.00733-12","article-title":"New parp gene with an anti-alphavirus function","volume":"86","author":"Atasheva","year":"2012","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.virol.2013.01.010","article-title":"Bst-2\/tetherin-mediated restriction of chikungunya (chikv) vlp budding is counteracted by chikv non-structural protein 1 (nsp1)","volume":"438","author":"Jones","year":"2013","journal-title":"Virology"},{"key":"ref_55","first-page":"068643","article-title":"Critical role for bst-2 in acute chikungunya virus infection","volume":"22","author":"Jones","year":"2014","journal-title":"J. Gen. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e163","DOI":"10.3389\/fmicb.2014.00163","article-title":"Counteraction of the multifunctional restriction factor tetherin","volume":"5","author":"Sauter","year":"2014","journal-title":"Front. Microbiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1242\/bio.20135793","article-title":"The cytosolic n-terminus of cd317\/tetherin is a membrane microdomain exclusion motif","volume":"2","author":"Billcliff","year":"2013","journal-title":"Biol. Open"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.chom.2014.08.005","article-title":"Retroviral retention activates a syk-dependent hemitam in human tetherin","volume":"16","author":"Galao","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.cell.2009.08.039","article-title":"Tetherin inhibits HIV-1 release by directly tethering virions to cells","volume":"139","author":"Zang","year":"2009","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"18428","DOI":"10.1073\/pnas.1011485107","article-title":"Structural insight into the mechanisms of enveloped virus tethering by tetherin","volume":"107","author":"Yang","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11645","DOI":"10.1128\/JVI.76.22.11645-11658.2002","article-title":"Placement of the structural proteins in sindbis virus","volume":"76","author":"Zhang","year":"2002","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"11078","DOI":"10.1128\/JVI.01390-12","article-title":"Cryo-electron tomography of rubella virus","volume":"86","author":"Battisti","year":"2012","journal-title":"J. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/nrmicro2559","article-title":"Herpesviruses remodel host membranes for virus egress","volume":"9","author":"Johnson","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"13115","DOI":"10.1128\/JVI.02167-13","article-title":"Herpes simplex virus 1 counteracts tetherin restriction via its virion host shutoff activity","volume":"87","author":"Zenner","year":"2013","journal-title":"J. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"13124","DOI":"10.1128\/JVI.02250-13","article-title":"Tetherin restricts herpes simplex virus 1 and is antagonized by glycoprotein m","volume":"87","author":"Blondeau","year":"2013","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1146\/annurev.cb.05.110189.001425","article-title":"Protein oligomerization in the endoplasmic reticulum","volume":"5","author":"Hurtley","year":"1989","journal-title":"Annu. Rev. Cell Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e80","DOI":"10.1186\/1742-4690-6-80","article-title":"The formation of cysteine-linked dimers of bst-2\/tetherin is important for inhibition of HIV-1 virus release but not for sensitivity to vpu","volume":"6","author":"Andrew","year":"2009","journal-title":"Retrovirology"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/7\/4\/2147\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:45:07Z","timestamp":1760215507000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/7\/4\/2147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,22]]},"references-count":67,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,4]]}},"alternative-id":["v7042147"],"URL":"https:\/\/doi.org\/10.3390\/v7042147","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,4,22]]}}}