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Updated: May 15, 2025

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TORC1 autonomously controls its spatial partitioning via the Rag GTPase tether Tco89.

Raffaele Nicastro1, Marie-Pierre Péli-Gulli1, Marco Caligaris1

  • 1Department of Biology, University of Fribourg, Fribourg, Switzerland.

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|May 13, 2025
PubMed
Summary

Yeast utilize Tco89 to tether TORC1 to Rag GTPases, regulating Sch9 kinase activity. TORC1 stabilizes Tco89 via phosphorylation, preventing its degradation and maintaining TORC1 localization for nutrient sensing.

Keywords:
CP: Cell biologyCP: Molecular biologyRag GTPasesTORC1Tco89amino acid signalinggrowth controltarget of rapamycin complex 1

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The target of rapamycin complex 1 (TORC1) is a crucial regulator of cell growth and homeostasis.
  • TORC1 integrates nutritional signals, particularly amino acid availability, within the endolysosomal system.
  • In mammals, the Rag GTPases recruit TORC1 to lysosomes via the Raptor subunit, a process essential for activation.

Purpose of the Study:

  • To investigate the mechanism by which yeast TORC1 is recruited to active Rag GTPases.
  • To identify the yeast ortholog responsible for tethering TORC1 to Rag GTPases in the absence of the mammalian Raptor claw domain.
  • To elucidate how TORC1 regulates its effector kinase Sch9 in response to amino acid availability.

Main Methods:

  • Genetic analysis in yeast (Saccharomyces cerevisiae).
  • Phosphorylation site mapping and proteolysis studies.
  • Subcellular localization assays using microscopy.
  • Biochemical assays to assess kinase activity.

Main Results:

  • Yeast employ the fungal-specific protein Tco89 to tether TORC1 to active Rag GTPases, unlike the mammalian Raptor claw domain.
  • Tco89 acts as a scaffold, enabling TORC1 to phosphorylate and stabilize itself, thereby calibrating Sch9 kinase activity.
  • TORC1 inactivation leads to Tco89 proteolysis, causing TORC1 redistribution from the vacuole to signaling endosomes and spatial uncoupling from Sch9.

Conclusions:

  • Yeast TORC1 utilizes Tco89 for lysosomal recruitment, demonstrating a conserved but distinct mechanism from mammals.
  • TORC1 dynamically controls Tco89 stability and its own subcellular localization to adapt to nutrient fluctuations.
  • This spatial regulation allows for energy conservation by spatially separating TORC1 from its effectors when nutrients are scarce.