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GATOR1-dependent recruitment of FLCN–FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids

Meng, Jin, Ferguson, Shawn M.·2018·Journal of Cell Biology
DOI 10.1083/jcb.201712177PMC PMC6080935
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Abstract

Folliculin (FLCN) is a tumor suppressor that coordinates cellular responses to changes in amino acid availability via regulation of the Rag guanosine triphosphatases. FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). The FLCN–FNIP heterodimer also has GTPase-activating protein (GAP) activity toward RagC/D. These properties raised two important questions. First, how is amino acid availability sensed to regulate lysosomal abundance of FLCN? Second, what is the relationship between FLCN lysosome localization, RagA/B interactions, and RagC/D GAP activity? In this study, we show that RagA/B nucleotide status determines the FLCN–FNIP1 recruitment to lysosomes. Starvation-induced FLCN–FNIP lysosome localization requires GAP activity toward Rags 1 (GATOR1), the GAP that converts RagA/B to the guanosine diphosphate (GDP)-bound state. This places FLCN–FNIP recruitment to lysosomes under the control of amino acid sensors that act upstream of GATOR1. By binding to RagA/BGDP and acting on RagC/D, FLCN–FNIP can coordinate nucleotide status between Rag heterodimer subunits in response to changes in amino acid availability.

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  • The FLCN complex acts as a GAP for RagC and RagD.

    “The regulation of RagC and RagD is somewhat less well understood, but the FLCN complex has been shown to act as a GAP for these GTPases 174–177.”

    From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [175]

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Metadata

Authors
Meng, J., & Ferguson, S. M.
Affiliations
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 1
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2018-05-30
Volume
217
Issue
8
Pages
2765-2776
ISSN
  • 0021-9525
  • 1540-8140
DOI
10.1083/jcb.201712177
PMC
PMC6080935
Cited by
75
References
13
Language
en
Licence
Funders
  • National Institutes of Health (GM105718, AG047270)
  • Ellison Medical Foundation

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