Feedback Inhibition of the Rag GTPase GAP Complex Lst4-Lst7 Safeguards TORC1 from Hyperactivation by Amino Acid Signals
Open accessAbstract
Amino acids stimulate the eukaryotic target of rapamycin complex 1 (TORC1), and hence growth, through the Rag GTPases and their regulators. Among these, the yeast Lst4-Lst7 Rag GTPase GAP complex clusters, as we previously reported, at the vacuolar membrane upon amino acid starvation. In response to amino acid refeeding, it activates the Rag GTPase-TORC1 branch and is then dispersed from the vacuolar surface. Here, we show that the latter effect is driven by TORC1 itself, which directly phosphorylates several residues within the intra-DENN loop of Lst4 that, only in its non-phosphorylated state, tethers the Lst4-Lst7 complex to the vacuolar membrane. An Lst4 variant disrupting this feedback inhibition mechanism causes TORC1 hyperactivation and proliferation defects in cells grown on poor nitrogen sources. Thus, we identify Lst4 as a TORC1 target and key node of a homeostatic mechanism that adjusts TORC1 activity to the availability of amino acids.
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In S. cerevisiae, TORC1 phosphorylation sites within Lst4, within an intra-DENN loop insertion, are involved in the release of the Lst4-Lst7 complex from the vacuolar membrane in response to nutrient repletion.
“A more recent study on S. cerevisiae Lst4 and Lst7 characterized TORC1 phosphorylation sites within Lst4 – within an intra-DENN loop insertion – which is involved in the release of the Lst4-Lst7 complex from the vacuolar membrane in response to nutrient repletion (Péli-Gulli et al., 2017).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Péli-Gulli et al., 2017
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- Authors
- Péli-Gulli, M.-P., Raucci, S., Hu, Z., Dengjel, J., & De Virgilio, C.
- Affiliations
- University of Fribourg (CH)
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 20
- Issue
- 2
- Pages
- 281-288
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2734490934
- Cited by
- 28
- References
- 26
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 6 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 6
- FWCI
- 1.12
- 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)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Canton de Fribourg
- 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
- TORC1, Rag GTPases, product inhibition, amino acid signaling, tonoplast, nitrogen homeostasis, cell proliferation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Microscopy, Fluorescence, Phosphorylation, Saccharomyces cerevisiae, Mass Spectrometry, Transcription Factors, Signal Transduction, Saccharomyces cerevisiae Proteins, Vesicular Transport Proteins, Immunoprecipitation
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