In vivo antagonistic role of the Human T-Cell Leukemia Virus Type 1 regulatory proteins Tax and HBZ
| العنوان: | In vivo antagonistic role of the Human T-Cell Leukemia Virus Type 1 regulatory proteins Tax and HBZ |
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| المؤلفون: | Hiba El Hajj, Rita Hleihel, Abdou Akkouche, Ali Bazarbachi, Séverine Chambeyron, Hala Skayneh, Sara Moodad |
| المساهمون: | American University of Beirut [Beyrouth] (AUB), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| المصدر: | PLoS Pathogens PLoS Pathogens, Public Library of Science, 2021, 17 (1), pp.e1009219. ⟨10.1371/journal.ppat.1009219⟩ PLoS Pathogens, Vol 17, Iss 1, p e1009219 (2021) |
| بيانات النشر: | HAL CCSD, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | RNA viruses, Life Cycles, Hemocytes, T-cell leukemia, Retroviridae Proteins, Pathology and Laboratory Medicine, Biochemistry, White Blood Cells, RNA interference, Larvae, 0302 clinical medicine, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, Biology (General), Cellular Senescence, Regulation of gene expression, Human T-lymphotropic virus 1, 0303 health sciences, biology, Drosophila Melanogaster, EZH2, Eukaryota, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Animal Models, Gene Products, tax, Precipitation Techniques, 3. Good health, Cell biology, Nucleic acids, Insects, Basic-Leucine Zipper Transcription Factors, Genetic interference, Experimental Organism Systems, Medical Microbiology, Viral Pathogens, 030220 oncology & carcinogenesis, Viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Epigenetics, Drosophila, Cellular Types, Anatomy, Pathogens, PRC2, Research Article, Gene Expression Regulation, Viral, Arthropoda, QH301-705.5, Immune Cells, Transgene, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Research and Analysis Methods, Transfection, Microbiology, 03 medical and health sciences, Model Organisms, Ocular System, Virology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Retroviruses, Genetics, Animals, Immunoprecipitation, Humans, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Transcription factor, 030304 developmental biology, Blood Cells, Biology and life sciences, Organisms, Cell Biology, Htlv-1, RC581-607, Invertebrates, HTLV-I Infections, Animal Studies, biology.protein, RNA, Eyes, Parasitology, Gene expression, Immunologic diseases. Allergy, Head, Zoology, Entomology, Developmental Biology, HeLa Cells |
| الوصف: | Adult T cell leukemia (ATL) is an aggressive malignancy secondary to chronic infection by the human T-cell leukemia virus type 1 (HTLV-1) infection. Two viral proteins, Tax and HBZ, play central roles in ATL leukemogenesis. Tax expression transforms T cells in vitro and induces ATL-like disease in mice. Tax also induces a rough eye phenotype and increases hemocyte count in Drosophila melanogaster, indicative of transformation. Among multiple functions, Tax modulates the expression of the enhancer of zeste homolog 2 (EZH2), a methyltransferase of the Polycomb Repressive Complex 2 (PRC2), leading to H3K27me3-dependent reprogramming of around half of cellular genes. HBZ is a negative regulator of Tax-mediated viral transcription. HBZ effects on epigenetic signatures are underexplored. Here, we established an hbz transgenic fly model, and demonstrated that, unlike Tax, which induces NF-κB activation and enhanced PRC2 activity creating an activation loop, HBZ neither induces transformation nor NF-κB activation in vivo. However, overexpression of Tax or HBZ increases the PRC2 activity and both proteins directly interact with PRC2 complex core components. Importantly, overexpression of HBZ in tax transgenic flies prevents Tax-induced NF-κB or PRC2 activation and totally rescues Tax-induced transformation and senescence. Our results establish the in vivo antagonistic effect of HBZ on Tax-induced transformation and cellular effects. This study helps understanding long-term HTLV-1 persistence and cellular transformation and opens perspectives for new therapeutic strategies targeting the epigenetic machinery in ATL. Author summary Adult T cell leukemia-lymphoma is an aggressive hematological malignancy, caused by the retroviral infection with HTLV-1. Tax and HBZ play critical roles in leukemia development. Tax activates the NF-κB pathway and modulates the epigenetic machinery to induce cellular proliferation and malignant transformation. We generated hbz or tax/hbz transgenic fly models and explored the phenotypes and epigenetic changes in vivo. Unlike Tax, HBZ expression failed to activate NF-κB or to induce transformation or senescence in vivo, yet activated PRC2 core components resulting in subsequent epigenetic changes. HBZ expression in tax Tg flies inhibits Tax-induced NF-κB or PRC2 activation, resulting in inhibition of malignant cellular proliferation and its consequent senescence. Our study proves the antagonistic effect of HBZ on Tax-induced transformation in vivo, providing further understanding on ATL pathogenesis. |
| اللغة: | English |
| تدمد: | 1553-7366 1553-7374 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7c543f8201aa64eeb246b79696cc85afTest https://hal.archives-ouvertes.fr/hal-03147929/file/journal.ppat.1009219.pdfTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7c543f8201aa64eeb246b79696cc85af |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537366 15537374 |
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