{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:42:39Z","timestamp":1790797359034,"version":"4.1.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG26195"],"award-info":[{"award-number":["IG26195"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["FP7_602893"],"award-info":[{"award-number":["FP7_602893"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004099","name":"Ligue Contre le Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004097","name":"Fondation ARC pour la Recherche sur le Cancer","doi-asserted-by":"publisher","award":["PJA20191209513"],"award-info":[{"award-number":["PJA20191209513"]}],"id":[{"id":"10.13039\/501100004097","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Adult T-cell leukemia\/lymphoma (ATL) is a T-cell lymphoproliferative neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). Two viral proteins, Tax-1 and HBZ play important roles in HTLV-1 infectivity and in HTLV-1-associated pathologies by altering key pathways of cell homeostasis. However, the molecular mechanisms through which the two viral proteins, particularly HBZ, induce and\/or sustain the oncogenic process are still largely elusive. Previous results suggested that HBZ interaction with nuclear factors may alter cell cycle and cell proliferation. To have a more complete picture of the HBZ interactions, we investigated in detail the endogenous HBZ interactome in leukemic cells by immunoprecipitating the HBZ-interacting complexes of ATL-2 leukemic cells, followed by tandem mass spectrometry analyses. RNA seq analysis was performed to decipher the differential gene expression and splicing modifications related to HTLV-1. Here we compared ATL-2 with MOLT-4, a non HTLV-1 derived leukemic T cell line and further compared with HBZ-induced modifications in an isogenic system composed by Jurkat T cells and stably HBZ transfected Jurkat derivatives. The endogenous HBZ interactome of ATL-2 cells identified 249 interactors covering three main clusters corresponding to protein families mainly involved in mRNA splicing, nonsense-mediated RNA decay (NMD) and JAK-STAT signaling pathway. Here we analyzed in detail the cluster involved in RNA splicing. RNAseq analysis showed that HBZ specifically altered the transcription of many genes, including crucial oncogenes, by affecting different splicing events. Consistently, the two RNA helicases, members of the RNA splicing family, DDX5 and its paralog DDX17, recently shown to be involved in alternative splicing of cellular genes after NF-\u03baB activation by HTLV-1 Tax-1, interacted and partially co-localized with HBZ. For the first time, a complete picture of the endogenous HBZ interactome was elucidated. The wide interaction of HBZ with molecules involved in RNA splicing and the subsequent transcriptome alteration strongly suggests an unprecedented complex role of the viral oncogene in the establishment of the leukemic state.<\/jats:p>","DOI":"10.3389\/fimmu.2022.939863","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T06:47:26Z","timestamp":1659336446000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing"],"prefix":"10.3389","volume":"13","author":[{"given":"Mariam","family":"Shallak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Alberio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Fasano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Monti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Iacobucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Ladet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Mortreux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto S.","family":"Accolla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta","family":"Forlani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.77.12.7415","article-title":"Detection and isolation of type c retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma","volume":"77","author":"Poiesz","year":"1980","journal-title":"Proc Natl Acad Sci USA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V50.3.481.481","article-title":"Adult T-cell leukemia: Clinical and hematologic features of 16 cases","volume":"50","author":"Uchiyama","year":"1977","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(85)92734-5","article-title":"Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis","volume":"2","author":"Gessain","year":"1985","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(86)91298-5","article-title":"HTLV-I associated myelopathy, a new clinical entity","volume":"327","author":"Osame","year":"1986","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s12977-019-0504-z","article-title":"Molecular epidemiology, genetic variability and evolution of HTLV-1 with special emphasis on African genotypes","volume":"16","author":"Afonso","year":"2019","journal-title":"Retrovirology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.1993.tb02832.x","article-title":"Transmission routes of HTLV-I: An analysis of 66 families","volume":"84","author":"Take","year":"1993","journal-title":"Jpn J Cancer Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-018-0658-4","article-title":"A review of new findings in adult T-cell leukemia\u2013lymphoma: A focus on current and emerging treatment strategies","volume":"35","author":"Hermine","year":"2018","journal-title":"Adv Ther"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.01425","article-title":"The exceptional oncogenicity of HTLV-1","volume":"8","author":"Tagaya","year":"2017","journal-title":"Front Microbiol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2111","article-title":"Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation","volume":"7","author":"Matsuoka","year":"2007","journal-title":"Nat Rev Cancer"},{"key":"B10","doi-asserted-by":"publisher","first-page":"8001","DOI":"10.3390\/ijms22158001","article-title":"HTLV-1 infection and pathogenesis: New insights from cellular and animal models","volume":"22","author":"Forlani","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B11","doi-asserted-by":"publisher","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":"B12","doi-asserted-by":"publisher","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":"B13","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1186\/1742-4690-2-64","article-title":"Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms","volume":"2","author":"Taniguchi","year":"2005","journal-title":"Retrovirology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3415","article-title":"Integrated molecular analysis of adult T cell leukemia\/lymphoma","volume":"47","author":"Kataoka","year":"2015","journal-title":"Nat Genet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1715724115","article-title":"Sporadic on\/off switching of HTLV-1 tax expression is crucial to maintain the whole population of virus-induced leukemic cells","volume":"115","author":"Mahgoub","year":"2018","journal-title":"Proc Natl Acad Sci"},{"key":"B16","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/1742-4690-5-34","article-title":"Characteristic expression of HTLV-1 basic zipper factor (HBZ) transcripts in HTLV-1 provirus-positive cells","volume":"5","author":"Usui","year":"2008","journal-title":"Retrovirology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s12977-020-0511-0","article-title":"HTLV-1 bZIP factor: The key viral gene for pathogenesis","volume":"17","author":"Matsuoka","year":"2020","journal-title":"Retrovirology"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2013.08.010","article-title":"Human T-cell leukemia virus type 1: Replication, proliferation and propagation by tax and HTLV-1 bZIP factor","volume":"3","author":"Matsuoka","year":"2013","journal-title":"Curr Opin Virol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s12977-015-0186-0","article-title":"Localization, quantification and interaction with host factors of endogenous HTLV-1 HBZ protein in infected cells and ATL","volume":"12","author":"Raval","year":"2015","journal-title":"Retrovirology."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005285","article-title":"Cytoplasmic localization of HTLV-1 HBZ protein: A biomarker of HTLV-1-Associated Myelopathy\/Tropical spastic paraparesis (HAM\/TSP)","volume":"11","author":"Baratella","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00819","article-title":"HTLV-1 HBZ protein resides exclusively in the cytoplasm of infected cells in asymptomatic carriers and HAM\/TSP patients","volume":"10","author":"Forlani","year":"2019","journal-title":"Front Microbiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.272468","article-title":"Dual cytoplasmic and nuclear localization of HTLV-1-encoded HBZ protein is a unique feature of adult T-cell leukemia","volume":"106","author":"Forlani","year":"2021","journal-title":"Haematologica."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1084\/jem.162.6.2169","article-title":"Origin of human T-lymphotrophic virus I-positive T cell lines in adult T cell leukemia. analysis of T cell receptor gene rearrangement","volume":"162","author":"Maeda","year":"1985","journal-title":"J Exp Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0238037","article-title":"New label-free methods for protein relative quantification applied to the investigation of an animal model of huntington disease","volume":"15","author":"Cozzolino","year":"2020","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddab047","article-title":"ADAM10 hyperactivation acts on piccolo to deplete synaptic vesicle stores in huntington\u2019s disease","volume":"30","author":"Cozzolino","year":"2021","journal-title":"Hum Mol Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1136800","article-title":"Clustering by passing messages between data points","volume":"315","author":"Frey","year":"2007","journal-title":"Science."},{"key":"B27","doi-asserted-by":"publisher","first-page":"8.13.1","DOI":"10.1002\/0471250953.bi0813s47","article-title":"Biological network exploration with cytoscape 3","volume":"47","author":"Su","year":"2014","journal-title":"Curr Protoc Bioinf"},{"key":"B28","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/1742-4690-3-15","article-title":"HTLV-I antisense transcripts initiating in the 3\u2019LTR are alternatively spliced and polyadenylated","volume":"3","author":"Cavanagh","year":"2006","journal-title":"Retrovirology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"4307","DOI":"10.1038\/s41598-018-21770-7","article-title":"Complementarity of assembly-first and mapping-first approaches for alternative splicing annotation and differential analysis from RNAseq data","volume":"8","author":"Benoit-Pilven","year":"2018","journal-title":"Sci Rep"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2013a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00480-06","article-title":"Human T-cell leukemia virus type 1 (HTLV-1) bZIP protein interacts with the cellular transcription factor CREB to inhibit HTLV-1 transcription","volume":"81","author":"Lemasson","year":"2007","journal-title":"J Virol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"12849","DOI":"10.1038\/s41598-017-12924-0","article-title":"HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia","volume":"7","author":"Takiuchi","year":"2017","journal-title":"Sci Rep"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1101\/gr.212696.116","article-title":"Identification of protein features encoded by alternative exons using exon ontology","volume":"27","author":"Tranchevent","year":"2017","journal-title":"Genome Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.13467","article-title":"MALT-1 as a novel therapeutic target for adult T-cell leukemia","volume":"105","author":"Ishikawa","year":"2020","journal-title":"Eur J Haematol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1186\/s13059-019-1869-y","article-title":"Characterizing the interplay between gene nucleotide composition bias and splicing","volume":"20","author":"Lemaire","year":"2019","journal-title":"Genome Biol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"3045","DOI":"10.1038\/s41467-020-16853-x","article-title":"Intragenic recruitment of NF-\u03baB drives splicing modifications upon activation by the oncogene tax of HTLV-1","volume":"11","author":"Ameur","year":"2020","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2009.113","article-title":"P68 RNA helicase is a nucleocytoplasmic shuttling protein","volume":"19","author":"Wang","year":"2009","journal-title":"Cell Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009919","article-title":"The HTLV-1 viral oncoproteins tax and HBZ reprogram the cellular mRNA splicing landscape","volume":"17","author":"Vandermeulen","year":"2021","journal-title":"PLoS Pathog"},{"key":"B40","doi-asserted-by":"publisher","first-page":"239","DOI":"10.3390\/cells10020239","article-title":"Aberrant splicing events and epigenetics in viral oncogenomics: Current therapeutic strategies","volume":"10","author":"Francies","year":"2021","journal-title":"Cells"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/emi.2014.62","article-title":"Oncogenes and RNA splicing of human tumor viruses","volume":"3","author":"Ajiro","year":"2014","journal-title":"Emerging Microbes Infect"},{"key":"B42","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1186\/s12977-014-0119-3","article-title":"HTLV-1-infected CD4+ T-cells display alternative exon usages that culminate in adult T-cell leukemia","volume":"11","author":"Th\u00e9noz","year":"2014","journal-title":"Retrovirology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"11292","DOI":"10.1038\/ncomms11292","article-title":"Alternative splicing of MALT1 controls signalling and activation of CD4+ T cells","volume":"7","author":"Meininger","year":"2016","journal-title":"Nat Commun"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.50","article-title":"The multiple functions of RNA helicases as drivers and regulators of gene expression","volume":"17","author":"Bourgeois","year":"2016","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506139102","article-title":"Sequence conservation, relative isoform frequencies, and nonsense-mediated decay in evolutionarily conserved alternative splicing","volume":"102","author":"Baek","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1101\/gad.332270.119","article-title":"Recurrent SRSF2 mutations in MDS affect both splicing and NMD","volume":"34","author":"Rahman","year":"2020","journal-title":"Genes Dev"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00356","article-title":"IL-2\/IL-2 receptor pathway plays a crucial role in the growth and malignant transformation of HTLV-1-Infected T cells to develop adult T-cell leukemia","volume":"11","author":"Maeda","year":"2020","journal-title":"Front Microbiol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/JCI150472","article-title":"HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia\/lymphoma","volume":"131","author":"Tan","year":"2021","journal-title":"J Clin Invest"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.939863\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T06:47:33Z","timestamp":1659336453000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.939863\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,1]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2022.939863"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.939863","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,1]]},"article-number":"939863"}}