Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing
Abstract
How organisms recover from starvation to nutrient-replete physiology remains poorly understood. In C. elegans, we previously observed that transcription factor hlh-30 or a combination of glucose and linoleic acid in its absence are essential for survival with refeeding following starvation, i.e. recovery competence. A forward genetic screen to evaluate mechanisms identified depd-5, which encodes a GATOR1 subunit, loss of which is expected to impair amino acid sensing with unrestrained raga-1 and mTOR activation. Surprisingly, glucose refeeding reduced recovery competence in depd-5(lf, loss-of-function) animals, which was rescued by amino acids, specifically tryptophan. Increasing tryptophan levels in depd-5(lf) worms through supplementation, reduced tryptophan catabolism with tdo-2 ablation and prolonged starvation restored recovery competence. raga-1(gf, gain-of-function) recapitulated whereas raga-1(lf) rescued the impaired recovery competence in starved depd-5(lf) worms. An analogous DEPDC5 mutation in mammalian cells impaired starvation-induced mTOR inactivation. We conclude that tryptophan counters unrestrained mTOR activity to restore recovery competence following starvation.
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BibTeX
@misc{murphy2026tryptophan,
title = {{Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing}},
author = {John T. Murphy and Ryan Chang and Ziang Bi and Siana Kapoor and Haoying Zhang and David Seamons and Agastya Diwan and Micklaus Garcia and Moydul Islam and Kenji Rowel Q. Lim and Daniel L. Schneider and Brian M. Egan and David Rawnsley and Xiucui Ma and Kerry Kornfeld and Abhinav Diwan},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762351},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762351v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing
AU - John T. Murphy
AU - Ryan Chang
AU - Ziang Bi
AU - Siana Kapoor
AU - Haoying Zhang
AU - David Seamons
AU - Agastya Diwan
AU - Micklaus Garcia
AU - Moydul Islam
AU - Kenji Rowel Q. Lim
AU - Daniel L. Schneider
AU - Brian M. Egan
AU - David Rawnsley
AU - Xiucui Ma
AU - Kerry Kornfeld
AU - Abhinav Diwan
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762351
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762351v1
AB - How organisms recover from starvation to nutrient-replete physiology remains poorly understood. In C. elegans, we previously observed that transcription factor hlh-30 or a combination of glucose and linoleic acid in its absence are essential for survival with refeeding following starvation, i.e. recovery competence. A forward genetic screen to evaluate mechanisms identified depd-5, which encodes a GATOR1 subunit, loss of which is expected to impair amino acid sensing with unrestrained raga-1 and mTOR activation. Surprisingly, glucose refeeding reduced recovery competence in depd-5(lf, loss-of-function) animals, which was rescued by amino acids, specifically tryptophan. Increasing tryptophan levels in depd-5(lf) worms through supplementation, reduced tryptophan catabolism with tdo-2 ablation and prolonged starvation restored recovery competence. raga-1(gf, gain-of-function) recapitulated whereas raga-1(lf) rescued the impaired recovery competence in starved depd-5(lf) worms. An analogous DEPDC5 mutation in mammalian cells impaired starvation-induced mTOR inactivation. We conclude that tryptophan counters unrestrained mTOR activity to restore recovery competence following starvation.
SN - 2692-8205
ER -