title: Inhibition of mTORC1 Enhances the Translation of Chikungunya Proteins via the Activation of the MnK/eIF4E Pathway.
abstract: Chikungunya virus (CHIKV), the causative agent of a major epidemic spanning five continents, is a positive stranded mRNA virus that replicates using the cell's cap-dependent translation machinery. Despite viral infection inhibiting mTOR, a metabolic sensor controls cap-dependent translation, viral proteins are efficiently translated. Rapalog treatment, silencing of mtor or raptor genes, but not rictor, further enhanced CHIKV infection in culture cells. Using biochemical assays and real time imaging, we demonstrate that this effect is independent of autophagy or type I interferon production. Providing in vivo evidence for the relevance of our findings, mice treated with mTORC1 inhibitors exhibited increased lethality and showed a higher sensitivity to CHIKV. A systematic evaluation of the viral life cycle indicated that inhibition of mTORC1 has a specific positive effect on viral proteins, enhancing viral replication by increasing the translation of both structural and nonstructural proteins. Molecular analysis defined a role for phosphatidylinositol-3 kinase (PI3K) and MAP kinase-activated protein kinase (MnKs) activation, leading to the hyper-phosphorylation of eIF4E. Finally, we demonstrated that in the context of CHIKV inhibition of mTORC1, viral replication is prioritized over host translation via a similar mechanism. Our study reveals an unexpected bypass pathway by which CHIKV protein translation overcomes viral induced mTORC1 inhibition.
authors: Unité Immunobiologie des Cellules Dendritiques, Département d'Immunologie, Institut Pasteur, Paris, Cedex 15, France; INSERM U818, Paris, France.
authors: Pierre-Emmanuel
authors: PE
authors: Joubert
authors: Unité des populations virales et Pathogenèse, Département de Virologie, Institut Pasteur, Paris, Cedex 15, France.
authors: Kenneth
authors: K
authors: Stapleford
authors: Unité Virus et Immunité, Département de Virologie Institut Pasteur, Paris, Cedex 15, France.
authors: Florence
authors: F
authors: Guivel-Benhassine
authors: Unité des populations virales et Pathogenèse, Département de Virologie, Institut Pasteur, Paris, Cedex 15, France.
authors: Marco
authors: M
authors: Vignuzzi
authors: Unité Virus et Immunité, Département de Virologie Institut Pasteur, Paris, Cedex 15, France.
authors: Olivier
authors: O
authors: Schwartz
authors: Unité Immunobiologie des Cellules Dendritiques, Département d'Immunologie, Institut Pasteur, Paris, Cedex 15, France; INSERM U818, Paris, France; Centre d'Immunologie Humaine, Département d'Immunologie, Institut Pasteur, Paris, Cedex 15, France.
authors: Matthew L
authors: ML
authors: Albert
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D065632:Chikungunya Fever / Q000378:metabolism*; D002646:Chikungunya virus / Q000378:metabolism; D004195:Disease Models, Animal; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D006790:Host-Parasite Interactions / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014162:Transfection; D014764:Viral Proteins / Q000096:biosynthesis*
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D014764:Viral Proteins; C000601282:eIF4E protein, mouse