Sensing of extracellular L-proline availability by the integrated stress response determines the outcome of cell competition
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Cell competition is a conserved fitness quality control that eliminates cells that are less-fit than their neighbours. How winner cells induce the elimination of losers is poorly understood. We tackle this question by studying the onset of differentiation in mice, where cell competition eliminates 35% of embryonic cells. These loser cells have mitochondrial dysfunction, which we show causes amino acid deprivation and activation of the integrated stress response (ISR), a pathway essential for their survival. We demonstrate that L-Proline is a key amino acid sensed by the ISR and that, in a Proline, that represses the ISR and drives their elimination. These results indicate that cell
competition acts as a novel tissue sparing mechanism, regulated by the availability of extracellular amino acids, that allows for the elimination of dysfunctional cells when amino acids are plentiful but ensures their survival in nutrient-poor environments.
competition acts as a novel tissue sparing mechanism, regulated by the availability of extracellular amino acids, that allows for the elimination of dysfunctional cells when amino acids are plentiful but ensures their survival in nutrient-poor environments.
Date Issued
2025-07-01
Date Acceptance
2025-06-03
Citation
Science Advances, 2025, 11 (28)
ISSN
2375-2548
Publisher
American Association for the Advancement of Science (AAAS)
Journal / Book Title
Science Advances
Volume
11
Issue
28
Copyright Statement
© 2025 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
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Publication Status
Published
Article Number
eadw1883
Date Publish Online
2025-07-09