Inhibition of mTORC1 Enhances the Translation of Chikungunya Proteins via the Activation of the MnK/eIF4E Pathway

• Published in: PLoS pathogens Vol. 11; no. 8; p. e1005091
• Main Authors: Joubert, Pierre-Emmanuel, Stapleford, Kenneth, Guivel-Benhassine, Florence, Vignuzzi, Marco, Schwartz, Olivier, Albert, Matthew L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-08-2015; Public Library of Science (PLoS)
• Subjects: Animals; Autophagy; Blotting, Northern; Blotting, Western; Cellular Biology; Chikungunya Fever - metabolism; Chikungunya virus; Chikungunya virus - metabolism; Disease Models, Animal; Epidemics; Eukaryotic Initiation Factor-4E - metabolism; Experiments; Flow Cytometry; Gene Knockout Techniques; Genetic aspects; Genetic translation; Genomes; Health aspects; Host-Parasite Interactions - physiology; Host-virus relationships; Infections; Interferon; Kinases; Life Sciences; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes - metabolism; Observations; Pathogenesis; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Protein Biosynthesis; Proteins; Real time; RNA, Small Interfering; Signal Transduction; Studies; TOR Serine-Threonine Kinases - metabolism; Transfection; Viral infections; Viral proteins; Viral Proteins - biosynthesis
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005091

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.