1. PDZ domain-binding motif of Tax sustains T-cell proliferation in HTLV-1-infected humanized mice
- Author
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Pérès, Eléonore, Blin, Juliana, Ricci, Emiliano P., Artesi, Maria, Hahaut, Vincent, Van den Broeke, Anne, Corbin, Antoine, Gazzolo, Louis, Ratner, Lee, Jalinot, Pierre, Duc Dodon, Madeleine, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Contrôle traductionnel des ARNm eucaryotes et viraux – Translational control of Eukaryotic and Viral RNAs, Centre International de Recherche en Infectiologie (CIRI), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Experimental Hematology, Université libre de Bruxelles (ULB)-Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB), Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, BioInformatique et BioStatistiques (BIBS), Washington University in Saint Louis (WUSTL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
- Subjects
RNA viruses ,Male ,Physiology ,T-Lymphocytes ,PDZ Domains ,Pathology and Laboratory Medicine ,Virologie générale ,Cell Transformation ,Lymphocyte Activation ,White Blood Cells ,Mice ,Animal Cells ,Immune Physiology ,Immunologie ,Medicine and Health Sciences ,Viral ,lcsh:QH301-705.5 ,Cytoskeleton ,Oncogene Proteins ,Parasitologie ,Human T-lymphotropic virus 1 ,T Cells ,tax ,Cell Polarity ,Gene Products, tax ,Body Fluids ,Blood ,Medical Microbiology ,Viral Pathogens ,Viruses ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,293T cells ,Cell lines ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Cellular Types ,Pathogens ,Anatomy ,Cellular Structures and Organelles ,Biological cultures ,Biologie ,Research Article ,Protein Binding ,lcsh:Immunologic diseases. Allergy ,Cell Physiology ,Immune Cells ,Immunology ,Microbiology ,Extraction techniques ,Retroviruses ,Animals ,Gene Products ,Humans ,Microbial Pathogens ,Cell Proliferation ,Blood Cells ,Animal ,Gene Expression Profiling ,Organisms ,Virologie médicale ,Biology and Life Sciences ,Biologie moléculaire ,Cell Biology ,Htlv-1 ,Oncogene Proteins, Viral ,Cell Transformation, Viral ,HTLV-I Infections ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,RNA extraction ,Research and analysis methods ,Disease Models, Animal ,HEK293 Cells ,lcsh:Biology (General) ,Disease Models ,lcsh:RC581-607 ,Microbiologie et protistologie [bacteriol.virolog.mycolog.] ,Spleen - Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive malignant proliferation of activated CD4+ T lymphocytes. The viral Tax oncoprotein is critically involved in both HTLV-1-replication and T-cell proliferation, a prerequisite to the development of ATLL. In this study, we investigated the in vivo contribution of the Tax PDZ domain-binding motif (PBM) to the lymphoproliferative process. To that aim, we examined T-cell proliferation in humanized mice (hu-mice) carrying a human hemato-lymphoid system infected with either a wild type (WT) or a Tax PBM-deleted (ΔPBM) provirus. We observed that the frequency of CD4+ activated T-cells in the peripheral blood and in the spleen was significantly higher in WT than in ΔPBM hu-mice. Likewise, human T-cells collected from WT hu-mice and cultivated in vitro in presence of interleukin-2 were proliferating at a higher level than those from ΔPBM animals. We next examined the association of Tax with the Scribble PDZ protein, a prominent regulator of T-cell polarity, in human T-cells analyzed either after ex vivo isolation or after in vitro culture. We confirmed the interaction of Tax with Scribble only in T-cells from the WT hu-mice. This association correlated with the presence of both proteins in aggregates at the leading edge of the cells and with the formation of long actin filopods. Finally, data from a comparative genome-wide transcriptomic analysis suggested that the PBM-PDZ association is implicated in the expression of genes regulating proliferation, apoptosis and cytoskeletal organization. Collectively, our findings suggest that the Tax PBM is an auxiliary motif that contributes to the sustained growth of HTLV-1 infected T-cells in vivo and in vitro and is essential to T-cell immortalization., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2018