Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2
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Rag GTPases assemble into heterodimeric complexes consisting of RagA or RagB and RagC or RagD in higher eukaryotes, or Gtr1 and Gtr2 in yeast, to relay amino acid signals toward the growth-regulating target of rapamycin complex 1 (TORC1). The TORC1-stimulating state of Rag GTPase heterodimers, containing GTP- and GDP-loaded RagA/B/Gtr1 and RagC/D/Gtr2, respectively, is maintained in part by the FNIP-Folliculin RagC/D GAP complex in mammalian cells. Here, we report the existence of a similar Lst4-Lst7 complex in yeast that functions as a GAP for Gtr2 and that clusters at the vacuolar membrane in amino acid-starved cells. Refeeding of amino acids, such as glutamine, stimulated the Lst4-Lst7 complex to transiently bind and act on Gtr2, thereby entailing TORC1 activation and Lst4-Lst7 dispersal from the vacuolar membrane. Given the remarkable functional conservation of the RagC/D/Gtr2 GAP complexes, our findings could be relevant for understanding the glutamine addiction of mTORC1-dependent cancers.
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Endogenous FLCN-FNIP1/2 and Lst4-Lst7 complexes exhibit lysosomal or vacuolar localization during nutrient deficiency, and once there FLCN-FNIP2 acts as the GAP for RagC/D.
“Endogenous FLCN-FNIP1/2 and Lst4-Lst7 complexes exhibit lysosomal or vacuolar localization during nutrient deficiency, respectively (Petit et al., 2013; Tsun et al., 2013; Péli-Gulli et al., 2015), and once there FLCN-FNIP2 acts as the GAP for RagC/D.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Péli-Gulli et al., 2015
An obligate FLCN-FNIP complex is necessary for the Rag interaction, since RagA and RagC coimmunoprecipitate with FLCN only when FNIP2 is coexpressed, and this interaction is strengthened during nutrient starvation and resulted in inhibition of (m)TORC1 activity.
“An obligate FLCN-FNIP complex is necessary for the Rag interaction, since RagA and RagC coimmunoprecipitate with FLCN only when FNIP2 is coexpressed, and this interaction is strengthened during nutrient starvation and resulted in inhibition of (m)TORC1 activity (Tsun et al., 2013; Péli-Gulli et al., 2015).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Péli-Gulli et al., 2015
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- Authors
- Péli-Gulli, M.-P., Sardu, A., Panchaud, N., Raucci, S., & De Virgilio, C.
- Affiliations
- University of Fribourg (CH)
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 13
- Issue
- 1
- Pages
- 1-7
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2121211842
- Cited by
- 157
- References
- 34
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 7 · 2023: 13 · 2022: 10 · 2021: 15 · 2020: 11 · 2019: 13 · 2018: 20 · 2017: 25 · 2016: 27 · 2015: 5
- FWCI
- 11.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Rag GTPases, GTPase-activating protein, amino acid signaling, glutamine, tonoplast, amino acid starvation, glutamine addiction
- MeSH terms
- Amino Acids, Binding Sites, Glutamine, Intracellular Membranes, Protein Binding, Saccharomyces cerevisiae, Transcription Factors, Vacuoles, Signal Transduction, Gene Expression Regulation, Fungal, Monomeric GTP-Binding Proteins, Protein Transport, Saccharomyces cerevisiae Proteins, Vesicular Transport Proteins, Protein Multimerization
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