Year: 2024
Type: article
Abstract: Animals must sense and respond to nutrient availability in their local niche. This task is coordinated in part by the mTOR complex 1 (mTORC1) pathway, which regulates growth and metabolism in response to nutrients 1-5 . In mammals, mTORC1 senses specific amino acids through specialized sensors that act through the upstream GATOR1/2 signaling hub 6-8 . To reconcile the conserved architecture of the mTORC1 pathway with the diversity of environments that animals can occupy, we hypothesized that the pathway might maintain plasticity by evolving distinct nutrient sensors in different metazoan phyla 1,9,10 . Whether such customization occurs— and how the mTORC1 pathway might capture new nutrient inputs—is not known. Here, we identify the Drosophila melanogaster protein Unmet expectations (Unmet, formerly CG11596) as a species-restricted nutrient sensor and trace its incorporation into the mTORC1 pathway. Upon methionine starvation, Unmet binds to the fly GATOR2 complex to inhibit dTORC1. S -adenosylmethionine (SAM), a proxy for methionine availability, directly relieves this inhibition. Unmet expression is elevated in the ovary, a methionine-sensitive niche 11 , and flies lacking Unmet fail to maintain the integrity of the female germline under methionine restriction. By monitoring the evolutionary history of the Unmet-GATOR2 interaction, we show that the GATOR2 complex evolved rapidly in Dipterans to recruit and repurpose an independent methyltransferase as a SAM sensor. Thus, the modular architecture of the mTORC1 pathway allows it to co-opt preexisting enzymes and expand its nutrient sensing capabilities, revealing a mechanism for conferring evolvability on an otherwise highly conserved system.
Source: Nature Communications
Institutions: Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, Howard Hughes Medical Institute, Harvard University, Inserm, Institut de Recherche en Cancérologie de Montpellier, Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: Howard Hughes Medical Institute, U.S. Department of Health and Human Services, Cystinosis Research Foundation, Lustgarten Foundation, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1003084024, G2952266551, Regulation of the mTOR Pathway by Nutrients, Cell Growth Signaling in Cancer Development, Characterization of the Insulin to Autophagy Pathway in Muscles, Determining the mechanism of serine sensing by the mTOR pathway, G6962561824, G7042930901, G7210776860, Pre-Doctoral Training in Biological Sciences, G7542484234, G7951081053, Novel Components of the mTORC1 and mTORC2 Pathways, G9000332944, Molecular Pathogenesis of the Hamartoma Syndromes
OpenAlex ID: W4393046801