Krishnan Shruthi, Lima Ana, Tan Sizhe, Low Ying Thong, Perez Montero Salvador, Di Gregorio Aida, Perez Barreto Adrian, Bowling Sarah, Vousden Karen, Rodriguez Tristan A
National Heart and Lung Institute, Imperial College London, London, UK.
The Francis Crick Institute, London, UK.
Sci Adv. 2025 Jul 11;11(28):eadw1883. doi: 10.1126/sciadv.adw1883. Epub 2025 Jul 9.
Cell competition is a conserved fitness quality control that eliminates cells that are less fit than their neighbors. How winner cells induce the elimination of losers is poorly understood. We tackle this question by studying the onset of embryonic 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 proline represses the ISR and drives their elimination. These results indicate that cell competition acts as a previously unidentified 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.
细胞竞争是一种保守的适应性质量控制机制，可消除比其邻居适应性差的细胞。获胜细胞如何诱导失败者的消除，目前尚不清楚。我们通过研究小鼠胚胎分化的起始来解决这个问题，在这个过程中，细胞竞争会消除35%的胚胎细胞。这些失败者细胞存在线粒体功能障碍，我们发现这会导致氨基酸缺乏并激活整合应激反应（ISR），这是它们生存所必需的一条途径。我们证明L-脯氨酸是ISR感知的关键氨基酸，脯氨酸会抑制ISR并促使它们被消除。这些结果表明，细胞竞争作为一种以前未被识别的组织保护机制，受细胞外氨基酸可用性的调节，在氨基酸丰富时允许消除功能失调的细胞，但在营养匮乏的环境中确保它们的存活。
