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

PLoS Pathogens
Pierre-Emmanuel JoubertMatthew L Albert

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 inhib...Continue Reading

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May 28, 2016·Viruses·Valerie Le SageAndrew J Mouland
Aug 9, 2016·Annual Review of Virology·Eric JanDerek Walsh
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Apr 25, 2020·Cells·Eline Van Huizen, Gerald M McInerney
Jun 19, 2019·PLoS Pathogens·Alessandra Soares-SchanoskiHelder I Nakaya
Nov 30, 2019·Molecular and Cellular Biochemistry·Asiya BatoolKhurshid Iqbal Andrabi
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Feb 4, 2021·Parasitology Research·Sajad RashidiRaúl Manzano-Román
Dec 16, 2018·International Journal of Biological Macromolecules·Asiya BatoolKhurshid Iqbal Andrabi

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Methods Mentioned

BETA
FACS
flow cytometry
transfection
FCS
electrophoresis
PCR
In Vitro Transcription
flow cytometery

Software Mentioned

TORISEL
FlowJo
IncuCyte ZOOM

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