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Rôle fonctionnel de protéines cellulaires interagissant avec la polymérase du virus de la rage

Abstract : The transcription and replication of the rabies virus are performed by the polymerase (L), an RNA dependant RNA polymerase, in cellular inclusions induced by the virus: the Negri Bodies (NB). During early infection, there is only one or two NB per cell (primary NB), growing with time up to their dispersion in several smaller NB (secondary NB). The NB concentrates all viral and cellular proteins necessary for the viral replication. Although several regulatory mechanisms between involved viral proteins are well described, the nature and role of cellular partners remain largely unknown. A yeast two-hybrid screening of a human cDNA library has identified cellular partners of the rabies L protein, in particular the hStaufen 1 protein. A mapping of the interaction showed that the Cterminal part of both proteins are required. During rabies infection, hStaufen 1, uniformly present in the cytoplasm, is reorganized in granular structures close to the NB, including back and forth movements with furtive contacts. This dynamics of hStaufen 1 is evocative of an intermediate role between NB and stress granules (SG) induced by rabies virus infection. Knock down of hStaufen 1 in the cell leads to increased amounts of intracellular viral proteins, to the inhibition of secondary NB formation and to a decrease of the budding and virion release from cell. This indicates that hStaufen 1 plays a major role in the microtubule-dependent intracellular transport of the newly synthesized ribonucleocapsids up to the site of budding. Three other L protein partners discovered during the two-hybrid screening have also been studied: eEF1A1 (eukaryotic translation elongation factor 1 alpha 1); hnRNPH2 (Heterogeneous Nuclear Ribonucleoprotein) ; TGFβ1I1 (Transforming growth factor beta-1-induced transcript 1 protein). Preliminary results suggest that they are somehow involved in the rabies virus replicative cycle, from transcription/replication inside NB to rabies virus release in the external environment.
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Clément Jousselin. Rôle fonctionnel de protéines cellulaires interagissant avec la polymérase du virus de la rage. Médecine humaine et pathologie. Sorbonne Université, 2019. Français. ⟨NNT : 2019SORUS153⟩. ⟨tel-02950926⟩

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