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HIV-1 enhances mTORC1 activity and repositions lysosomes to the periphery by co-opting Rag GTPases.

HIV-1 enhances mTORC1 activity and repositions lysosomes to the periphery by co-opting Rag GTPases.
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Cinti A, Le Sage V, Milev MP, Valiente-Echeverría F, Crossie C, Miron MJ, Panté N, Olivier M, Mouland AJ,


Cinti A, Le Sage V, Milev MP, Valiente-Echeverría F, Crossie C, Miron MJ, Panté N, Olivier M, Mouland AJ, (click to view)

Cinti A, Le Sage V, Milev MP, Valiente-Echeverría F, Crossie C, Miron MJ, Panté N, Olivier M, Mouland AJ,

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Scientific reports 2017 07 147(1) 5515 doi 10.1038/s41598-017-05410-0

Abstract

HIV-1 co-opts several host machinery to generate a permissive environment for viral replication and transmission. In this work we reveal how HIV-1 impacts the host translation and intracellular vesicular trafficking machineries for protein synthesis and to impede the physiological late endosome/lysosome (LEL) trafficking in stressful conditions. First, HIV-1 enhances the activity of the master regulator of protein synthesis, the mammalian target of rapamycin (mTOR). Second, the virus commandeers mTOR-associated late endosome/lysosome (LEL) trafficking and counteracts metabolic and environmental stress-induced intracellular repositioning of LEL. We then show that the small Rag GTPases, RagA and RagB, are required for the HIV-1-mediated LEL repositioning that is likely mediated by interactions between the Rags and the viral proteins, Gag and Vif. siRNA-mediated depletion of RagA and RagB leads to a loss in mTOR association to LEL and to a blockade of viral particle assembly and release at the plasma membrane with a marked concomitant reduction in virus production. These results show that HIV-1 co-opts fundamental mechanisms that regulate LEL motility and positioning and support the notion that LEL positioning is critical for HIV-1 replication.

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