Sestrin mediates detection of and adaptation to low-leucine diets in Drosophila

• Published in: Nature (London) Vol. 608; no. 7921; pp. 209 - 216
• Main Authors: Gu, Xin, Jouandin, Patrick, Lalgudi, Pranav V., Binari, Rich, Valenstein, Max L., Reid, Michael A., Allen, Annamarie E., Kamitaki, Nolan, Locasale, Jason W., Perrimon, Norbert, Sabatini, David M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.08.2022; Nature Publishing Group
• Subjects: 14; 14/19; 631/443/319/1488; 631/45/612; 64/24; 82/80; 96/95; Adaptation, Physiological - genetics; Amino acids; Animal Feed; Animals; Autophagy; Binding; Diet; Diet - veterinary; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - deficiency; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Flies; Food; Food Preferences; Glial cells; Humanities and Social Sciences; Insects; Kinases; Leucine; Leucine - deficiency; Leucine - metabolism; Life span; Mammalian cells; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; multidisciplinary; Mutant Proteins - genetics; Mutant Proteins - metabolism; Neuroglia - metabolism; Nutrient deficiency; Nutrients; Progeny; Proteins; Rapamycin; Science; Science (multidisciplinary); Sestrins - deficiency; Sestrins - genetics; Sestrins - metabolism; Signal Transduction; Starvation; TOR protein
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-022-04960-2

Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple nutrients, including the essential amino acid leucine 1 . Recent work in cultured mammalian cells established the Sestrins as leucine-binding proteins that inhibit mTORC1 signalling during leucine deprivation 2 , 3 , but their role in the organismal response to dietary leucine remains elusive. Here we find that Sestrin -null flies ( Sesn −/− ) fail to inhibit mTORC1 or activate autophagy after acute leucine starvation and have impaired development and a shortened lifespan on a low-leucine diet. Knock-in flies expressing a leucine-binding-deficient Sestrin mutant ( Sesn L431E ) have reduced, leucine-insensitive mTORC1 activity. Notably, we find that flies can discriminate between food with or without leucine, and preferentially feed and lay progeny on leucine-containing food. This preference depends on Sestrin and its capacity to bind leucine. Leucine regulates mTORC1 activity in glial cells, and knockdown of Sesn in these cells reduces the ability of flies to detect leucine-free food. Thus, nutrient sensing by mTORC1 is necessary for flies not only to adapt to, but also to detect, a diet deficient in an essential nutrient. Fruitflies require Sestrin to regulate mTORC1 signalling in response to dietary leucine, survive a diet low in leucine, and control leucine-sensitive physiological characteristics, which establishes Sestrin as a physiologically relevant leucine sensor.