Augmenting intracellular amino acid pools suppresses the phenotypes of autophagy-deficient cells.

Authors

Rubén Barrios, Rebeca Gracia-Domingo, Cristina Corral-Ramos, Élida Alechaga, Óscar J Pozo, José Ayté, Elena Hidalgo

Published in

Autophagy. Pages 1-17. Sep 07, 2026. Epub Sep 07, 2026.

Abstract

TORC1 is a central regulator of cell growth whose inactivation under conditions of nutrient deprivation triggers adaptive responses, including macroautophagy/autophagy, amino acid uptake, and sexual differentiation. Autophagy-deficient fission yeast cells display mating defects and are unable to recover from amino acid starvation, even when external amino acids are available. Here, we investigate how TORC1 signaling and autophagy interact to control these processes. We show that both major phenotypes of autophagy-deficient cells - their inability to resume growth after amino acid starvation and their mating defects - stem from insufficient intracellular amino acid pools. Genetic or environmental enhancement of intracellular amino acid pools alleviates both defects. During leucine starvation, deletion of any1 rescues the growth defect of atg1Δ mutants by maintaining amino acid transporters at the plasma membrane, promoting amino acid uptake. Importantly, we uncover a previously unrecognized role for autophagy in the cell-cycle remodeling required for sexual differentiation. Nitrogen depletion-mediated TORC1 inactivation initiates these cell-cycle rearrangements required to start the mating/meiosis program, but autophagy is specifically required for the final G2-to-G1 arrest that precedes the program. This step correlates with the accumulation of the cyclin-dependent kinase inhibitor Rum1. Metabolomic analyses reveal that intracellular amino acid pools drop sharply during nitrogen starvation, especially in autophagy-deficient cells, and supplementation with trace amino acids restores their ability to complete the final G2-to-G1 transition. Together, our results reveal that autophagy sustains intracellular amino acid pools during prolonged stress, enabling TORC1 reactivation and cell-cycle remodeling necessary for successful mating and meiosis.Abbreviations: DNA: deoxyribonucleic acid; FACS: fluorescence-activated cell sorting; GATOR1: GAP activity toward Rags 1; GATOR2: GAP activity toward Rags 2; GFP: green fluorescent protein; MM: minimal medium; N: nitrogen; PCR: polymerase chain reaction; RNA: ribonucleic acid; S. cerevisiae: Saccharomyces cerevisiae; S. pombe: Schizosaccharomyces pombe; TOR: target of rapamycin; TORC1: target of rapamycin complex 1; TORC2: target of rapamycin complex 2; tRNA: transfer ribonucleic acid; YE5S: yeast extract 5 amino acid supplemented; WT: wild-type.

PMID:
42706721
Bibliographic data and abstract were imported from PubMed on 08 Sep 2026.

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