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

Xin Gu (), Patrick Jouandin (), Pranav V. Lalgudi, Rich Binari, Max L. Valenstein, Michael A. Reid, Annamarie E. Allen, Nolan Kamitaki, Jason W. Locasale, Norbert Perrimon () and David M. Sabatini
Additional contact information
Xin Gu: Whitehead Institute for Biomedical Research
Patrick Jouandin: Blavatnik Institute, Harvard Medical School
Pranav V. Lalgudi: Whitehead Institute for Biomedical Research
Rich Binari: Blavatnik Institute, Harvard Medical School
Max L. Valenstein: Whitehead Institute for Biomedical Research
Michael A. Reid: Duke University School of Medicine
Annamarie E. Allen: Duke University School of Medicine
Nolan Kamitaki: Blavatnik Institute, Harvard Medical School
Jason W. Locasale: Duke University School of Medicine
Norbert Perrimon: Blavatnik Institute, Harvard Medical School

Nature, 2022, vol. 608, issue 7921, 209-216

Abstract: Abstract Mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple nutrients, including the essential amino acid leucine1. Recent work in cultured mammalian cells established the Sestrins as leucine-binding proteins that inhibit mTORC1 signalling during leucine deprivation2,3, 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 (SesnL431E) 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.

Date: 2022
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DOI: 10.1038/s41586-022-04960-2

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