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

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The ongoing chikungunya epidemic outbreak in the Caribbean, Central and South America highlights how poor is our understanding of CHIKV pathogenesis and the urgent need for new strategies that may limit CHIKV spread. Immunological studies have suggested that dissemination of infection is largely determined by early events of viral-host cell interactions. In our prior study, we investigated the role of type I interferon responses and the autophagy pathway as mediators of viral control. Here, we evaluated the role of mTOR, making the surprising discovery that inhibition of mTORC1 enhances viral protein translation independently of type I IFN and autophagy. While the inhibition of mTORC1 has no impact on viral binding or entry, we observed an increased translation of both structural and nonstructural viral proteins. Interestingly, the positive impact of mTORC1 inhibition is restricted to viral proteins, as compared to host cap-dependent protein translation that remains suppressed. Further analysis demonstrates that this bypass pathway is mediated the activation of PI3K and MnKs, which in turn hyper-phosphorylate eIF4E, a critical initiation protein for translation. Notably, CHIKV replication enables this pathway as a means to efficiently replicate. Thus, our study provides an unexpected role for mTORC1 in the control of CHIKV infection and highlights a new strategy by which the expression of CHIKV proteins can bypass and/or use the inhibition of mTORC1.

Vyšlo v časopise: Inhibition of mTORC1 Enhances the Translation of Chikungunya Proteins the Activation of the MnK/eIF4E Pathway. PLoS Pathog 11(8): e32767. doi:10.1371/journal.ppat.1005091
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005091

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