Activation de la voie NF-kB par les protéines Tax des HTLV : Rôles des modifications post-traductionnelles et de la localisation de Tax

Abstract : Human T cell Leukemia Virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL), a CD4+ T-cell malignancy, Constitutive activation of the NF-KB pathway plays a crucial role in cell proliferation and transformation induced by HTLV-1, According to the classical model, Tax acts at two levels on the NF-KB pathway, In the cytoplasm, Tax activates the IKB kinase (IKK) complex by directly interacting with the regulatory subunit NEMO/IKKy, In the nucleus, Tax directly interacts with the NF-KB dimers in particular structures named Tax nuclear bodies, Both ubiquitinylation and SUMOylation were initially considered as critical for activation of the cytoplasmic or nuclear phase, respectively, However, the individual role of each modification was difficult to assess because of the lack of molecular tools allowing to study Tax ubiquitination and SUMOylation separately,In the laboratory, we functionally characterized a new Tax mutant, Tax-P 7 9AQ81A, which gave us the opportunity to uncouple Tax ubiquitination and SUMOylation, Indeed, Tax-P79AQ81A is ubiquitinated similarly to wild-type Tax but is severely reduced in SUMOylation, In addition, Tax- P 7 9AQ81A does not form nuclear bodies, However, despite these two severe defects, we found that the mutant is fully able to activate the NF-KB pathway not only in cells lines but also in CD4+ primary T cells, Moreover we showed that Tax nuclear bodies are hardly present in HTLV-1 chronically infected T cell lines, confirming the idea that these structures are not required for Tax-induced NF-KB activation and probably for other Tax functions, Finally, we demonstrated that ability of different Tax mutant to activate the NF-KB pathway is strongly correlated with their ubiquitination but not SUMOylation level, confirming that ubiquitination is the key Tax modification required for activation of the NF-KB pathway,In contrast to HTLV-1, the related HTLV-2 virus is not a transforming virus and therefore, the properties of the Tax2 protein compared to that of Tax1 could be responsible for the different pathogenicity of HTLV-2 and HTLV-1, We studied the post-translational modifications of Tax2 and surprisingly, found that Tax2-induced NF-KB activation is not only independent of SUMOylation and nuclear body formation but also of ubiquitination, suggesting different mechanisms of activation of the IKK complex by Tax1 and Tax2,In conclusion, our results led us to propose a new model for both Tax1- and Tax2-induced NF- KB activation in which SUMOylation has a minor role and in which the requirement of Tax ubiquitination distinguishes between HTLV-1 and HTLV-2
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Submitted on : Thursday, March 28, 2013 - 10:42:16 AM
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Amandine Bonnet. Activation de la voie NF-kB par les protéines Tax des HTLV : Rôles des modifications post-traductionnelles et de la localisation de Tax. Médecine humaine et pathologie. Université René Descartes - Paris V, 2012. Français. ⟨NNT : 2012PA05T069⟩. ⟨tel-00805542⟩



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