Sensing of extracellular L-Proline availability by the integrated stress response determines the outcome of cell competition
Year: 2024
Type: preprint
Abstract: Cell competition is a quality control acting from development to the adult that eliminates cells that are less-fit than their neighbours. How winner cells induce the elimination of losers during this process is poorly understood. Here, we address this question by studying the onset of differentiation in mouse, where cell competition eliminates 35% of embryonic cells. These loser cells have mitochondrial dysfunction, and we find that this causes amino-acid deprivation and activation of the integrated stress response (ISR), a pathway essential for their survival. We show that L-Proline is a key amino-acid sensed by the ISR and that in a competitive environment, winner cells induce increased L-Proline uptake in loser cells. This causes ISR repression and their elimination. Our results imply that cell competition is acting as a nutrient sensor, eliminating dysfunctional cells when amino acids are plentiful but sparing them in nutrient poor environments.
Authors: Shruthi Krishnan, Ana Lima, Ying Thong Low, Salvador Perez Montero, Sizhe Tan, Aida Di Gregorio, Adrian Perez Barreto, Sarah Bowling, Karen Vousden, Tristan A. Rodriguez
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: A Superresolution microscope for biological research in the multi-user Microscopy Facility [FILM]: ALERT 13, FILM microscopy facility: New generation confocal and high content screening microscopes, and upgrades for intravital microscopy., Understanding the mechanisms of aneuploid cell elimination during early mammalian development
OpenAlex ID: W4404801410