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Updated: May 3, 2026
Assay for Adhesion and Agar Invasion in S. cerevisiae
Published on: November 8, 2006
Endolysosomal membrane trafficking complexes drive nutrient-dependent TORC1 signaling to control cell growth in
Joanne M Kingsbury1, Neelam D Sen, Tatsuya Maeda
1Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
Abstract:
The rapamycin-sensitive and endomembrane-associated TORC1 pathway controls cell growth in response to nutrients in eukaryotes. Mutations in class C Vps (Vps-C) complexes are synthetically lethal with tor1 mutations and confer rapamycin hypersensitivity in Saccharomyces cerevisiae, suggesting a role for these complexes in TORC1 signaling. Vps-C complexes are required for vesicular trafficking and fusion and comprise four distinct complexes: HOPS and CORVET and their minor intermediaries (i)-CORVET and i-HOPS. We show that at least one Vps-C complex is required to promote TORC1 activity, with the HOPS complex having the greatest input. The vps-c mutants fail to recover from rapamycin-induced growth arrest and show low levels of TORC1 activity. TORC1 promotes cell growth via Sch9, a p70(S6) kinase ortholog. Constitutively active SCH9 or hyperactive TOR1 alleles restored rapamycin recovery and TORC1 activity of vps-c mutants, supporting a role for the Vps-C complexes upstream of TORC1. The EGO GTPase complex Exit from G0 Complex (EGOC) and its homologous Rag-GTPase complex convey amino acid signals to TORC1 in yeast and mammals, respectively. Expression of the activated EGOC GTPase subunits Gtr1(GTP) and Gtr2(GDP) partially suppressed vps-c mutant rapamycin recovery defects, and this suppression was enhanced by increased amino acid concentrations. Moreover, vps-c mutations disrupted EGOC-TORC1 interactions. TORC1 defects were more severe for vps-c mutants than those observed in EGOC mutants. Taken together, our results support a model in which distinct endolysosomal trafficking Vps-C complexes promote rapamycin-sensitive TORC1 activity via multiple inputs, one of which involves maintenance of amino acid homeostasis that is sensed and transmitted to TORC1 via interactions with EGOC.
Insights
Class C Vps (Vps-C) complexes are crucial for nutrient-sensing TORC1 pathway activity and cell growth. These endolysosomal trafficking complexes interact with the EGOC complex to maintain TORC1 signaling.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The Target of Rapamycin Complex 1 (TORC1) pathway regulates cell growth in response to nutrient availability in eukaryotes.
- Class C Vps (Vps-C) complexes are essential for vesicular trafficking and fusion, and mutations in these complexes lead to synthetic lethality with TORC1 pathway mutations and hypersensitivity to rapamycin.
- Vps-C complexes are implicated in TORC1 signaling, but their precise role remains unclear.
Purpose of the Study:
- To investigate the role of Vps-C complexes in regulating TORC1 pathway activity and cell growth.
- To determine the relationship between Vps-C complexes, TORC1, and the EGO GTPase complex (EGOC) in nutrient sensing.
- To elucidate the molecular mechanisms by which Vps-C complexes influence TORC1 signaling.
Main Methods:
- Genetic analysis of Vps-C mutants in Saccharomyces cerevisiae.
- Assessment of TORC1 activity and cell growth recovery after rapamycin treatment.
- Analysis of interactions between Vps-C complexes, TORC1, and the EGOC complex.
- Investigating the impact of altered amino acid concentrations on Vps-C mutant phenotypes.
Main Results:
- Vps-C complexes, particularly the HOPS complex, are required for promoting TORC1 activity and recovery from rapamycin-induced growth arrest.
- Vps-C mutants exhibit reduced TORC1 activity and fail to recover from growth arrest, which can be partially rescued by constitutively active SCH9 or hyperactive TOR1 alleles.
- Vps-C mutations disrupt the interaction between the EGOC complex and TORC1, and this defect is exacerbated under conditions of altered amino acid concentrations.
Conclusions:
- Distinct endolysosomal trafficking Vps-C complexes are essential for maintaining rapamycin-sensitive TORC1 activity.
- Vps-C complexes act upstream of TORC1, potentially by maintaining amino acid homeostasis and facilitating signal transmission via the EGOC complex.
- These findings reveal a critical role for Vps-C complexes in integrating nutrient signals for proper TORC1-mediated cell growth regulation.
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