{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:02:58Z","timestamp":1791306178263,"version":"4.3.1"},"reference-count":133,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2014,10,23]],"date-time":"2014-10-23T00:00:00Z","timestamp":1414022400000},"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":["RO1CA135362"],"award-info":[{"award-number":["RO1CA135362"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia\/lymphoma (ATLL) in 3%\u20135% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T-cell proliferation and cell survival. The Tax oncoprotein promotes T-cell transformation, in part via constitutive activation of the NF-\u03baB transcription factor; however, the underlying mechanisms remain unknown. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Emerging studies indicate that Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-\u03baB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine  63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. In addition to NF-\u03baB signaling, mono- and polyubiquitination of Tax also regulate its subcellular trafficking and stability. Here, we review recent advances in the diverse roles of ubiquitin in Tax function and how Tax usurps the ubiquitin-proteasome pathway to  promote oncogenesis.<\/jats:p>","DOI":"10.3390\/v6103925","type":"journal-article","created":{"date-parts":[[2014,10,23]],"date-time":"2014-10-23T12:28:28Z","timestamp":1414067308000},"page":"3925-3943","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Regulation of HTLV-1 Tax Stability, Cellular Trafficking and NF-\u03baB Activation by the Ubiquitin-Proteasome Pathway"],"prefix":"10.3390","volume":"6","author":[{"given":"Alfonso","family":"Lavorgna","sequence":"first","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center,  Johns Hopkins School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Harhaj","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center,  Johns Hopkins School of Medicine, Baltimore, MD 21287, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/S1473-3099(07)70081-6","article-title":"Human T-lymphotropic virus 1: Recent knowledge about an ancient infection","volume":"7","author":"Verdonck","year":"2007","journal-title":"Lancet. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1111\/j.1365-2141.1991.tb08051.x","article-title":"Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984\u201387)","volume":"79","author":"Shimoyama","year":"1991","journal-title":"Br. J. Haematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nm1745","article-title":"Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4(+) T cells","volume":"14","author":"Jones","year":"2008","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1128\/jcm.30.4.905-910.1992","article-title":"Infection of peripheral blood mononuclear cells and cell lines by cell-free human T-cell lymphoma\/leukemia virus type I","volume":"30","author":"Fan","year":"1992","journal-title":"J. Clin. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12692","DOI":"10.1128\/JVI.79.20.12692-12702.2005","article-title":"Heparan sulfate proteoglycans mediate attachment and entry of human T-cell leukemia virus type 1 virions into CD4+ T cells","volume":"79","author":"Jones","year":"2005","journal-title":"J. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6844","DOI":"10.1128\/JVI.02719-05","article-title":"Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry","volume":"80","author":"Ghez","year":"2006","journal-title":"J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S0092-8674(03)00881-X","article-title":"The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV","volume":"115","author":"Manel","year":"2003","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1126\/science.1080115","article-title":"Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton","volume":"299","author":"Igakura","year":"2003","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29653","DOI":"10.1074\/jbc.M502639200","article-title":"Human T-lymphotropic virus, type 1, tax protein triggers microtubule reorientation in the virological synapse","volume":"280","author":"Nejmeddine","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3389\/fmicb.2013.00271","article-title":"Highlights on distinctive structural and functional properties of HTLV Tax proteins","volume":"4","author":"Romanelli","year":"2013","journal-title":"Front. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7070","DOI":"10.1073\/pnas.89.15.7070","article-title":"Human T-cell lymphotropic virus type I (HTLV-I) transcriptional activator, Tax, enhances CREB binding to HTLV-I 21-base-pair repeats by protein-protein interaction","volume":"89","author":"Zhao","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1073\/pnas.92.4.1057","article-title":"Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I","volume":"92","author":"Grossman","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1126\/science.2888190","article-title":"The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice","volume":"237","author":"Nerenberg","year":"1987","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/nm1389","article-title":"Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I","volume":"12","author":"Hasegawa","year":"2006","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5976","DOI":"10.1038\/sj.onc.1208978","article-title":"Molecular mechanisms of cellular transformation by HTLV-1 Tax","volume":"24","author":"Grassmann","year":"2005","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1080\/15216540500078715","article-title":"Mechanisms of persistent NF-kappaB activation by HTLV-I tax","volume":"57","author":"Harhaj","year":"2005","journal-title":"IUBMB Life"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3001","DOI":"10.1128\/JVI.00086-10","article-title":"Complex cell cycle abnormalities caused by human T-lymphotropic virus type 1 Tax","volume":"85","author":"Yang","year":"2011","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1128\/MCB.20.10.3377-3386.2000","article-title":"Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-kappaB pathway and is dependent on p53 phosphorylation","volume":"20","author":"Mahieux","year":"2000","journal-title":"Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/sj.onc.1208105","article-title":"The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation","volume":"24","author":"Kehn","year":"2005","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/B978-0-12-394280-7.00003-8","article-title":"The multifaceted oncoprotein Tax: Subcellular localization, posttranslational modifications, and NF-kappaB activation","volume":"113","author":"Kfoury","year":"2012","journal-title":"Adv. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1128\/JVI.74.5.2351-2364.2000","article-title":"Human T-cell leukemia virus type 1 Tax shuttles between functionally discrete subcellular targets","volume":"74","author":"Burton","year":"2000","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/0042-6822(92)90320-O","article-title":"Characterization of a novel nuclear localization signal in the HTLV-I tax transactivator protein","volume":"187","author":"Smith","year":"1992","journal-title":"Virology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21814","DOI":"10.1074\/jbc.M211576200","article-title":"Characterization of a nuclear export signal within the human T cell leukemia virus type I transactivator protein Tax","volume":"278","author":"Alefantis","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6657","DOI":"10.1128\/JVI.02270-05","article-title":"Genotoxic stress and cellular stress alter the subcellular distribution of human T-cell leukemia virus type 1 tax through a CRM1-dependent mechanism","volume":"80","author":"Gatza","year":"2006","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17353","DOI":"10.1074\/jbc.M409851200","article-title":"Secretion of the human T cell leukemia virus type I transactivator protein tax","volume":"280","author":"Alefantis","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/intimm\/3.8.761","article-title":"Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic T cells directed against HTLV-I-infected cells","volume":"3","author":"Kannagi","year":"1991","journal-title":"Int. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nm984","article-title":"HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication","volume":"10","author":"Nicot","year":"2004","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3389\/fmicb.2013.00275","article-title":"The need to accessorize: Molecular roles of HTLV-1 p30 and HTLV-2 p28 accessory proteins in the viral life cycle","volume":"4","author":"Anupam","year":"2013","journal-title":"Front. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1073\/pnas.0507631103","article-title":"HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells","volume":"103","author":"Satou","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1182\/blood-2008-06-161729","article-title":"Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kappaB","volume":"113","author":"Zhao","year":"2009","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e1004040","DOI":"10.1371\/journal.ppat.1004040","article-title":"Regulation of human T-lymphotropic virus type I latency and reactivation by HBZ and Rex","volume":"10","author":"Philip","year":"2014","journal-title":"PLoS Pathog."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1001274","DOI":"10.1371\/journal.ppat.1001274","article-title":"HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo","volume":"7","author":"Satou","year":"2011","journal-title":"PLoS Pathog."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1101\/gad.183434.111","article-title":"NF-kappaB, the first quarter-century: Remarkable progress and outstanding questions","volume":"26","author":"Hayden","year":"2012","journal-title":"Genes Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/embr.201337983","article-title":"The IkappaB kinase complex in NF-kappaB regulation and beyond","volume":"15","author":"Hinz","year":"2014","journal-title":"EMBO Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/35085597","article-title":"TAK1 is a ubiquitin-dependent kinase of MKK and IKK","volume":"412","author":"Wang","year":"2001","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.molcel.2004.08.008","article-title":"TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains","volume":"15","author":"Kanayama","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1016\/j.cell.2009.03.007","article-title":"Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation","volume":"136","author":"Rahighi","year":"2009","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1146\/annurev.immunol.16.1.225","article-title":"NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses","volume":"16","author":"Ghosh","year":"1998","journal-title":"Annu. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1101\/gad.909001","article-title":"NF-kappaB signaling pathways in mammalian and insect innate immunity","volume":"15","author":"Silverman","year":"2001","journal-title":"Genes Dev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1023\/A:1023733231406","article-title":"Deregulation of NF-kappaB and its upstream kinases in cancer","volume":"22","author":"Sun","year":"2003","journal-title":"Cancer Metastasis Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/ni0302-221","article-title":"NF-kappaB at the crossroads of life and death","volume":"3","author":"Karin","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/cr.2010.177","article-title":"Non-canonical NF-kappaB signaling pathway","volume":"21","author":"Sun","year":"2011","journal-title":"Cell. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1600-065X.2011.01088.x","article-title":"The noncanonical NF-kappaB pathway","volume":"246","author":"Sun","year":"2012","journal-title":"Immunol. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S1097-2765(01)00187-3","article-title":"NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100","volume":"7","author":"Xiao","year":"2001","journal-title":"Mol. Cell."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1126\/science.1062677","article-title":"Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway","volume":"293","author":"Senftleben","year":"2001","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"30099","DOI":"10.1074\/jbc.M401428200","article-title":"Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation","volume":"279","author":"Xiao","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1038\/ni.1678","article-title":"Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling","volume":"9","author":"Vallabhapurapu","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/ni.1676","article-title":"Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK","volume":"9","author":"Zarnegar","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ccr.2007.07.003","article-title":"Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma","volume":"12","author":"Keats","year":"2007","journal-title":"Cancer Cell."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ccr.2007.07.004","article-title":"Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma","volume":"12","author":"Annunziata","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_51","first-page":"2360","article-title":"Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells","volume":"93","author":"Mori","year":"1999","journal-title":"Blood"},{"key":"ref_52","first-page":"7377","article-title":"Human T-cell leukemia virus type I Tax activation of NF-kappa B\/Rel involves phosphorylation and degradation of I kappa B alpha and RelA (p65)-mediated induction of the c-rel gene","volume":"14","author":"Sun","year":"1994","journal-title":"Mol. Cell. Biol"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6805","DOI":"10.1093\/emboj\/20.23.6805","article-title":"Retroviral oncoprotein Tax induces processing of NF-kappaB2\/p100 in T cells: Evidence for the involvement of IKKalpha","volume":"20","author":"Xiao","year":"2001","journal-title":"EMBO J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"22911","DOI":"10.1074\/jbc.274.33.22911","article-title":"IKKgamma serves as a docking subunit of the IkappaB kinase (IKK) and mediates interaction of IKK with the human T-cell leukemia virus Tax protein","volume":"274","author":"Harhaj","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"15297","DOI":"10.1074\/jbc.274.22.15297","article-title":"IKKgamma mediates the interaction of cellular IkappaB kinases with the tax transforming protein of human T cell leukemia virus type 1","volume":"274","author":"Chu","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"17402","DOI":"10.1074\/jbc.274.25.17402","article-title":"Role of adapter function in oncoprotein-mediated activation of NF-kappaB. Human T-cell leukemia virus type I Tax interacts directly with IkappaB kinase gamma","volume":"274","author":"Jin","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/sj.embor.7400931","article-title":"Retroviral oncoprotein Tax deregulates NF-kappaB by activating Tak1 and mediating the physical association of Tak1-IKK","volume":"8","author":"Wu","year":"2007","journal-title":"EMBO Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.bbrc.2007.03.125","article-title":"HTLV-1 Tax-induced NFkappaB activation is independent of Lys-63-linked-type polyubiquitination","volume":"357","author":"Gohda","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.virol.2010.08.023","article-title":"Association of HTLV Tax proteins with TAK1-binding protein 2 and RelA in calreticulin-containing cytoplasmic structures participates in Tax-mediated NF-kappaB activation","volume":"408","author":"Avesani","year":"2010","journal-title":"Virology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.bbrc.2007.10.172","article-title":"HTLV-1 Tax-mediated TAK1 activation involves TAB2 adapter protein","volume":"365","author":"Yu","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"25177","DOI":"10.1074\/jbc.C700065200","article-title":"Constitutive activation of TAK1 by HTLV-1 tax-dependent overexpression of TAB2 induces activation of JNK-ATF2 but not IKK-NF-kappaB","volume":"282","author":"Suzuki","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1128\/jvi.70.5.2730-2735.1996","article-title":"Persistent activation of NF-kappa B\/Rel by human T-cell leukemia virus type 1 tax involves degradation of I kappa B beta","volume":"70","author":"Good","year":"1996","journal-title":"J. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5952","DOI":"10.1038\/sj.onc.1208969","article-title":"Activation of NF-kappaB by HTLV-I and implications for cell transformation","volume":"24","author":"Sun","year":"2005","journal-title":"Oncogene"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4856","DOI":"10.1128\/JVI.73.6.4856-4865.1999","article-title":"Immortalization of CD4(+) and CD8(+) T lymphocytes by human T-cell leukemia virus type 1 Tax mutants expressed in a functional molecular clone","volume":"73","author":"Robek","year":"1999","journal-title":"J. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1126\/science.8456277","article-title":"Ablation of transplanted HTLV-I tax-transformed tumors in mice by antisense inhibition of NF-kappa B","volume":"259","author":"Kitajima","year":"1993","journal-title":"Science"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/sj.leu.2404129","article-title":"Induction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor","volume":"20","author":"Sanda","year":"2006","journal-title":"Leukemia"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"44563","DOI":"10.1074\/jbc.M403689200","article-title":"Tax deregulation of NF-kappaB2 p100 processing involves both beta-TrCP-dependent and -independent mechanisms","volume":"279","author":"Qu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"9474","DOI":"10.1128\/JVI.00158-12","article-title":"HTLV-1 tax-induced rapid senescence is driven by the transcriptional activity of NF-kappaB and depends on chronically activated IKKalpha and p65\/RelA","volume":"86","author":"Ho","year":"2012","journal-title":"J. Virol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"18137","DOI":"10.1074\/jbc.M401397200","article-title":"Human T-cell lymphotropic virus type 1 tax induction of biologically Active NF-kappaB requires IkappaB kinase-1-mediated phosphorylation of RelA\/p65","volume":"279","author":"Montano","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"11900","DOI":"10.1128\/JVI.00532-07","article-title":"Cooperation of NF-kappaB2\/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line","volume":"81","author":"Higuchi","year":"2007","journal-title":"J. Virol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1182\/blood-2010-08-303073","article-title":"The tumor suppressor gene WWOX links the canonical and noncanonical NF-kappaB pathways in HTLV-I Tax-mediated tumorigenesis","volume":"117","author":"Fu","year":"2011","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/1742-4690-6-83","article-title":"Identification of a novel motif responsible for the distinctive transforming activity of human T-cell leukemia virus (HTLV) type 1 Tax1 protein from HTLV-2 Tax2","volume":"6","author":"Shoji","year":"2009","journal-title":"Retrovirology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.virol.2003.10.006","article-title":"PDZ domain-binding motif of human T-cell leukemia virus type 1 Tax oncoprotein augments the transforming activity in a rat fibroblast cell line","volume":"318","author":"Hirata","year":"2004","journal-title":"Virology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6670","DOI":"10.1073\/pnas.94.13.6670","article-title":"Binding of human virus oncoproteins to hDlg\/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein","volume":"94","author":"Lee","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1593\/neo.03388","article-title":"Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells","volume":"6","author":"Hironaka","year":"2004","journal-title":"Neoplasia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/ijc.20007","article-title":"Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cells","volume":"109","author":"Takeda","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ccr.2011.12.015","article-title":"Polycomb-mediated loss of miR-31 activates NIK-dependent NF-kappaB pathway in adult T cell leukemia and other cancers","volume":"21","author":"Yamagishi","year":"2012","journal-title":"Cancer Cell."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.molcel.2009.01.014","article-title":"Nonproteolytic functions of ubiquitin in cell signaling","volume":"33","author":"Chen","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.devcel.2009.04.001","article-title":"Diversity of polyubiquitin chains","volume":"16","author":"Adhikari","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/embor.2009.144","article-title":"Linear polyubiquitination: A new regulator of NF-kappaB activation","volume":"10","author":"Iwai","year":"2009","journal-title":"EMBO Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1093\/jb\/mvt079","article-title":"Linear ubiquitination-mediated NF-kappaB regulation and its related disorders","volume":"154","author":"Tokunaga","year":"2013","journal-title":"J. Biochem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1146\/annurev.biochem.78.082307.091526","article-title":"Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes","volume":"78","author":"Ventii","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1146\/annurev.biochem.78.070907.102750","article-title":"The role of ubiquitin in NF-kappaB regulatory pathways","volume":"78","author":"Skaug","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nrm2731","article-title":"Breaking the chains: Structure and function of the deubiquitinases","volume":"10","author":"Komander","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/381328a0","article-title":"Effects on NF-kappa B1\/p105 processing of the interaction between the HTLV-1 transactivator Tax and the proteasome","volume":"381","author":"Rousset","year":"1996","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"S76","DOI":"10.1097\/00042560-199600001-00014","article-title":"Interaction of HTLV-I Tax with the human proteasome: Implications for NF-kappa B induction","volume":"13","author":"Beraud","year":"1996","journal-title":"J. Acquir. Immun. Defic. Syndr. Hum. Retrovirol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"11823","DOI":"10.1128\/JVI.78.21.11823-11832.2004","article-title":"Stable ubiquitination of human T-cell leukemia virus type 1 tax is required for proteasome binding","volume":"78","author":"Chiari","year":"2004","journal-title":"J. Virol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"11686","DOI":"10.1128\/JVI.78.21.11686-11695.2004","article-title":"Ubiquitination of human T-cell leukemia virus type 1 tax modulates its activity","volume":"78","author":"Peloponese","year":"2004","journal-title":"J. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/1742-4690-4-95","article-title":"Ubiquitination of HTLV-I Tax in response to DNA damage regulates nuclear complex formation and nuclear export","volume":"4","author":"Gatza","year":"2007","journal-title":"Retrovirology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"10391","DOI":"10.1128\/MCB.25.23.10391-10406.2005","article-title":"Exclusive ubiquitination and sumoylation on overlapping lysine residues mediate NF-kappaB activation by the human T-cell leukemia virus tax oncoprotein","volume":"25","author":"Lamsoul","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"13735","DOI":"10.1128\/JVI.01790-07","article-title":"The human T-cell leukemia virus type 1 Tax oncoprotein requires the ubiquitin-conjugating enzyme Ubc13 for NF-kappaB activation","volume":"81","author":"Shembade","year":"2007","journal-title":"J. Virol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e1000521","DOI":"10.1371\/journal.ppat.1000521","article-title":"NRP\/Optineurin Cooperates with TAX1BP1 to potentiate the activation of NF-kappaB by human T-lymphotropic virus type 1 tax protein","volume":"5","author":"Journo","year":"2009","journal-title":"PLoS Pathog."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"4185","DOI":"10.1074\/jbc.M611031200","article-title":"Activation of NF-kappaB by the human T cell leukemia virus type I Tax oncoprotein is associated with ubiquitin-dependent relocalization of IkappaB kinase","volume":"282","author":"Harhaj","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6208","DOI":"10.1074\/jbc.M806390200","article-title":"HTLV-1 Tax is a critical lipid raft modulator that hijacks IkappaB kinases to the microdomains for persistent activation of NF-kappaB","volume":"284","author":"Huang","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1038\/sj.onc.1210804","article-title":"Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome","volume":"27","author":"Kfoury","year":"2008","journal-title":"Oncogene"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1093\/jb\/mvr106","article-title":"Activation of the IkappaB kinase complex by HTLV-1 Tax requires cytosolic factors involved in Tax-induced polyubiquitination","volume":"150","author":"Shibata","year":"2011","journal-title":"J. Biochem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/1742-4690-9-103","article-title":"The importance of ubiquitination and sumoylation on the transforming activity of HTLV Tax-1 and Tax-2","volume":"9","author":"Zane","year":"2012","journal-title":"Retrovirology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"4021","DOI":"10.1182\/blood-2005-09-3572","article-title":"Tax ubiquitylation and sumoylation control critical cytoplasmic and nuclear steps of NF-kappaB activation","volume":"107","author":"Nasr","year":"2006","journal-title":"Blood"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"6347","DOI":"10.1128\/jvi.70.9.6347-6357.1996","article-title":"Localization of human T-cell leukemia virus type 1 tax to subnuclear compartments that overlap with interchromatin speckles","volume":"70","author":"Semmes","year":"1996","journal-title":"J. Virol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/1742-4690-9-77","article-title":"Low nuclear body formation and tax SUMOylation do not prevent NF-kappaB promoter activation","volume":"9","author":"Bonnet","year":"2012","journal-title":"Retrovirology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"10655","DOI":"10.1128\/JVI.01827-14","article-title":"A Non-SUMOylated Tax Protein Is Still Functional for NF-kappaB Pathway Activation","volume":"88","author":"Pene","year":"2014","journal-title":"J. Virol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/2045-3701-1-27","article-title":"Mutual regulation between deubiquitinase CYLD and retroviral oncoprotein Tax","volume":"1","author":"Wu","year":"2011","journal-title":"Cell Biosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3886","DOI":"10.1128\/MCB.25.10.3886-3895.2005","article-title":"Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation","volume":"25","author":"Reiley","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"6212","DOI":"10.1128\/JVI.00079-11","article-title":"Ubiquitin-specific peptidase 20 targets TRAF6 and human T cell leukemia virus type 1 tax to negatively regulate NF-kappaB signaling","volume":"85","author":"Yasunaga","year":"2011","journal-title":"J. Virol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/j.1600-065X.2012.01100.x","article-title":"Regulation of NF-kappaB by deubiquitinases","volume":"246","author":"Harhaj","year":"2012","journal-title":"Immunol. Rev."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/cr.2010.166","article-title":"Deubiquitinases in the regulation of NF-kappaB signaling","volume":"21","author":"Harhaj","year":"2011","journal-title":"Cell Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/emboj.2008.5","article-title":"Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-kappaB activation","volume":"27","author":"Iha","year":"2008","journal-title":"EMBO J."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3910","DOI":"10.1038\/sj.emboj.7601823","article-title":"Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling","volume":"26","author":"Shembade","year":"2007","journal-title":"EMBO J."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"8332","DOI":"10.1128\/JVI.72.10.8332-8337.1998","article-title":"CREB-2, a cellular CRE-dependent transcription repressor, functions in association with Tax as an activator of the human T-cell leukemia virus type 1 promoter","volume":"72","author":"Gachon","year":"1998","journal-title":"J. Virol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"4182","DOI":"10.1038\/sj.onc.1202787","article-title":"The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases","volume":"18","author":"Jin","year":"1999","journal-title":"Oncogene"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"9567","DOI":"10.1073\/pnas.170279097","article-title":"T6BP, a TRAF6-interacting protein involved in IL-1 signaling","volume":"97","author":"Ling","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/emboj.2008.285","article-title":"The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling","volume":"28","author":"Shembade","year":"2009","journal-title":"EMBO J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/ni1563","article-title":"The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20","volume":"9","author":"Shembade","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/ni.2066","article-title":"The kinase IKKalpha inhibits activation of the transcription factor NF-kappaB by phosphorylating the regulatory molecule TAX1BP1","volume":"12","author":"Shembade","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1126\/science.1182364","article-title":"Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes","volume":"327","author":"Shembade","year":"2010","journal-title":"Science"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Ren, T., Takahashi, Y., Liu, X., Loughran, T.P., Sun, S.C., Wang, H.G., and Cheng, H. (2013). HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains. Oncogene.","DOI":"10.1038\/onc.2013.552"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e50672","DOI":"10.1371\/journal.pone.0050672","article-title":"TBK1 kinase addiction in lung cancer cells is mediated via autophagy of Tax1bp1\/Ndp52 and non-canonical NF-kappaB signalling","volume":"7","author":"Newman","year":"2012","journal-title":"PLoS One"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"4370","DOI":"10.1182\/blood-2008-10-185660","article-title":"PDLIM2 suppresses human T-cell leukemia virus type I Tax-mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation","volume":"113","author":"Yan","year":"2009","journal-title":"Blood"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"13640","DOI":"10.1128\/JVI.02006-13","article-title":"HSP90 protects the human T-cell leukemia virus type 1 (HTLV-1) tax oncoprotein from proteasomal degradation to support NF-kappaB activation and HTLV-1 replication","volume":"87","author":"Gao","year":"2013","journal-title":"J. Virol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"e132","DOI":"10.1038\/bcj.2013.30","article-title":"Oral administration of an HSP90 inhibitor, 17-DMAG, intervenes tumor-cell infiltration into multiple organs and improves survival period for ATL model mice","volume":"3","author":"Ikebe","year":"2013","journal-title":"Blood Cancer J."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3357","DOI":"10.1128\/JVI.06456-11","article-title":"An RNA interference screen identifies the Deubiquitinase STAMBPL1 as a critical regulator of human T-cell leukemia virus type 1 tax nuclear export and NF-kappaB activation","volume":"86","author":"Lavorgna","year":"2012","journal-title":"J. Virol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1182\/blood-2011-06-358564","article-title":"The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax","volume":"119","author":"Fryrear","year":"2012","journal-title":"Blood"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"24445","DOI":"10.1074\/jbc.C000777200","article-title":"Persistent activation of NF-kappa B by the tax transforming protein involves chronic phosphorylation of IkappaB kinase subunits IKKbeta and IKKgamma","volume":"276","author":"Carter","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/S0014-5793(02)03590-1","article-title":"Stimulation of IKK-gamma oligomerization by the human T-cell leukemia virus oncoprotein Tax","volume":"531","author":"Huang","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"48903","DOI":"10.1074\/jbc.M310686200","article-title":"Signal-induced ubiquitination of I kappaB Kinase-beta","volume":"278","author":"Carter","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1074\/jbc.M210631200","article-title":"Human T-lymphotropic virus type I tax activates I-kappa B kinase by inhibiting I-kappa B kinase-associated serine\/threonine protein phosphatase 2A","volume":"278","author":"Fu","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"6480","DOI":"10.1128\/JVI.00036-11","article-title":"The human T-cell leukemia virus type 1 oncoprotein tax controls forkhead box O4 activity through degradation by the proteasome","volume":"85","author":"Oteiza","year":"2011","journal-title":"J. Virol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1073\/pnas.0406424101","article-title":"HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule","volume":"102","author":"Liu","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Choi, Y.B., and Harhaj, E.W. (2014). HTLV-1 Tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation. PLoS Pathog, In Press.","DOI":"10.1371\/journal.ppat.1004458"},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Lavorgna, A., Matsuoka, M., and Harhaj, E.W. (2014). A critical role for IL-17RB signaling in HTLV-1 Tax-induced NF-kB activation and T-cell transformation. PLoS Pathog., In Press.","DOI":"10.1186\/1742-4690-12-S1-P52"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.4049\/jimmunol.176.2.1013","article-title":"Involvement of TNF receptor-associated factor 6 in IL-25 receptor signaling","volume":"176","author":"Maezawa","year":"2006","journal-title":"J. Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"3875","DOI":"10.1182\/blood.V97.12.3875","article-title":"Comparative genomic hybridization analysis in adult T-cell leukemia\/lymphoma: Correlation with clinical course","volume":"97","author":"Tsukasaki","year":"2001","journal-title":"Blood"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1128\/JVI.01792-12","article-title":"Human T cell leukemia virus type 2 tax-mediated NF-kappaB activation involves a mechanism independent of Tax conjugation to ubiquitin and SUMO","volume":"87","author":"Bonnet","year":"2013","journal-title":"J. Virol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/6\/10\/3925\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:17:19Z","timestamp":1760217439000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/6\/10\/3925"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,23]]},"references-count":133,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2014,10]]}},"alternative-id":["v6103925"],"URL":"https:\/\/doi.org\/10.3390\/v6103925","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,23]]}}}