The rising demand for powerful oncolytic virotherapy agents has led to the identification of Maraba virus, one of the most potent oncolytic viruses from Rhabdoviridae family which displays high selectivity for killing malignant cells and low cytotoxicity in normal cells. Although the virus is readied to be used for clinical trials, the interactions between the virus and the host cells is still unclear. Using a newly developed interferon-sensitive mutant Maraba virus (MG1), we have identified two key regulators of global translation (4E-BP1 and eIF2α) responsible for the inhibition of protein synthesis in the infected cells. Despite the translational arrest upon viral stress, we showed an up-regulation of anti-apoptotic Bcl-xL protein that provides a survival benefit for the host cell, yet facilitates effective viral propagation. Given the fact that eIF5B canonically regulates 60S ribosome subunit end joining, and is able to replace the role of eIF2 in delivering initiator tRNA to the 40S ribosome subunit upon the phosphorylation of eIF2α, we have tested whether eIF5B mediates the translation of target mRNAs during MG1 infection. Our results show that the inhibition of eIF5B significantly down-regulates the level of Bcl-xL steady-state mRNA, thus indirectly attenuates viral propagation.

RACK1 (Receptor for activated protein C kinase 1) est une protéine ribosomale associée à de nombreuses voies de signalisation. RACK1 est nécessaire à la traduction sélective de virus contenant des sites d’entrée interne du ribosome (IRES). En outre, l’expression de RACK1 est nécessaire au cours du développement, suggérant que ce facteur participe à la traduction de certains ARNm cellulaires. Dans le but de mieux comprendre la fonction de RACK1 chez la drosophile, j’ai au cours de ma thèse caractérisé l’interactome de RACK1 et un IRES viral régulé par ce facteur. J’ai également essayé d’établir un lien entre signalisation cellulaire et traduction, et montré que la région du knob est importante pour la fonction de RACK1 au ribosome. Enfin, j’ai établi que RACK1 est nécessaire à la réponse à des stress abiotiques, et identifié les gènes cellulaires régulés par RACK1 dans ce contexte. J’ai en particulier découvert que RACK1 était un régulateur négatif de l’expression de plusieurs gènes de l’immunité innée. Mes résultats suggèrent que RACK1 joue un rôle pivot au sein du ribosome, régulant la traduction de façon positive ou négative selon l’ARNm et le contexte cellulaire. / RACK1 (Receptor for activated protein C kinase 1) is a ribosomal protein associated to many signaling pathways. RACK1 is required for the selective translation of viruses containing internal ribosome entry sites (IRES). In addition, expression of RACK1 is necessary during development, suggesting that it regulates the translation of cellular mRNAs. In order to better understand the function of RACK1 in Drosophila, I have participated in the characterization of the RACK1 interactome and of a RACK1-dependent viral IRES. I have also attempted to establish a connection between the function of RACK1 in signaling and in translation, and I have shown that the knob domain of RACK1 is important for IRES-dependent translation. Finally, I have established that RACK1 is required for the response to abiotic stresses, and I have identified cellular genes regulated by RACK1 in this context. In particular, I discovered that RACK1 is a negative regulator of several innate immunity genes. My results suggest that RACK1 plays a pivotal role within the ribosome, regulating translation positively or negatively in an mRNA- and possibly context-specific manner.