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

PLoS Pathogens

Kenneth Stapleford¹  Pierre-Emmanuel Joubert²  Matthew L. Albert³  Marco Vignuzzi³  Florence Guivel-Benhassine⁴  Olivier Schwartz⁴ 

[1] INSERM U818, Paris, France;Unité Immunobiologie des Cellules Dendritiques, Département d’Immunologie, Institut Pasteur, Paris, Cedex 15, France;Unité Virus et Immunité, Département de Virologie Institut Pasteur, Paris, Cedex 15, France;Unité des populations virales et Pathogenèse, Département de Virologie, Institut Pasteur, Paris, Cedex 15, France

关键词: Chikungunya infection;    Chikungunya virus;    Protein translation;    Viral replication;    Autophagic cell death;    Small interfering RNAs;    Phosphorylation;    Interferons;   

DOI  :  10.1371/journal.ppat.1005091

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY