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Metabolism

GPCRs join the mTORC1 regulatory network

Nature Cell Biology volume 21, pages 538–539 (2019)Cite this article

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Rag GTPases play a crucial role in mTORC1 activation by promoting its recruitment to the lysosomal surface in a nutrient-dependent manner. A study now identifies a family of lysosomal G-protein-coupled receptors as modulators of Rag GTPases localization and activation, adding one more component to the fast-growing mTOR regulatory network.

To identify regulators of mTORC1 activity and localization, Gan et al.5 took an unbiased approach and performed a microscopy-based genome-wide human siRNA screen. Over 21,000 pools of siRNA, each consisting of four siRNAs targeting individual genes, were initially tested in the non-transformed human fibroblasts cell line Hs68. More than 400 pools resulted in impaired mTORC1 activity, as assessed by reduced phosphorylation of the mTORC1 substrate rp60. To focus on proteins that specifically regulate mTORC1 distribution, the authors monitored mTORC1 colocalization with the lysosomal marker Lamp2 in cells starved and treated with cycloheximide, a means to rule out proteins that regulate amino acid uptake from outside the cell. This approach reduced the list to only 15 genes, with RRAGC as the top hit, in agreement with the well-known role of Rags in mTORC1 recruitment to lysosomes5.

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Fig. 1: Schematic showing regulation of mTORC1 in mammalian cells.

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  1. Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Rosa Puertollano

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  1. Rosa Puertollano
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Correspondence to Rosa Puertollano.

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Puertollano, R. GPCRs join the mTORC1 regulatory network. Nat Cell Biol 21, 538–539 (2019). https://doi.org/10.1038/s41556-019-0320-7

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