Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing

Murphy, J. T.; Chang, R.; Bi, Z.; Kapoor, S.; Zhang, H.; Seamons, D.; Diwan, A.; Garcia, M.; Islam, M.; Lim, K. R.; Schneider, D. L.; Egan, B. M.; Rawnsley, D. R.; Ma, X.; Kornfeld, K.

doi:10.64898/2026.10.27.762351

bioRxiv · 10.64898/2026.10.27.762351

Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing

Murphy, J. T.·Chang, R.·Bi, Z.·Kapoor, S.·Zhang, H.·Seamons, D.·Diwan, A.·Garcia, M.·Islam, M.·Lim, K. R.·Schneider, D. L.·Egan, B. M.·Rawnsley, D. R.·Ma, X.·Kornfeld, K.

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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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Murphy, J. T., Chang, R., Bi, Z., Kapoor, S., Zhang, H., Seamons, D., Diwan, A., Garcia, M., Islam, M., Lim, K. R., Schneider, D. L., Egan, B. M., Rawnsley, D. R., Ma, X., Kornfeld, K.. 2026-10-28. Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing. https://doi.org/10.64898/2026.10.27.762351

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