Multilayered regulation of TORC1 signaling by Ait1, Gcn2, and SEAC/GATOR during nitrogen limitation and starvation

Cristina M Padilla1, Jeaho Lim1, Austin A Lipinski2

  • 1Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA.

Nature Communications
|November 29, 2025
PubMed

Insights

Cellular nutrient sensing involves the Target of Rapamycin kinase Complex I (TORC1). Researchers found that Ait1, Gcn2, and SEAC proteins cooperate to regulate TORC1 activity during nitrogen scarcity, controlling cell growth and quiescence.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Target of Rapamycin kinase Complex I (TORC1) is a crucial regulator of cell growth and metabolism in eukaryotes.
  • Understanding how TORC1 signaling is precisely controlled by upstream factors under varying environmental conditions is essential.

Purpose of the Study:

  • To investigate the cooperative mechanisms of TORC1 upstream regulators in Saccharomyces cerevisiae during nutrient stress.
  • To elucidate the graded regulation of TORC1 activity in response to different nitrogen availability levels.

Main Methods:

  • Phosphoproteomics analysis to identify changes in protein phosphorylation.
  • TORC1 activity assays to measure kinase complex activity.
  • Targeted genetic perturbations to assess the roles of specific proteins.

Main Results:

  • During adaptation to low-quality nitrogen (proline), Ait1 and Gcn2 partially inhibit TORC1, leading to metabolic reprogramming without growth arrest.
  • Under nitrogen starvation, SEAC, Ait1, and Gcn2 collaborate to fully inhibit TORC1, inducing quiescence.
  • This study reveals a multilayered regulatory circuit for graded TORC1 control.

Conclusions:

  • TORC1 regulation is finely tuned by a network of proteins in response to nitrogen availability.
  • The identified regulatory circuit likely represents a conserved mechanism across eukaryotic organisms.
  • This research provides insights into cellular adaptation strategies to nutrient stress.

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