Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS, San Raffaele Scientific Institute, Milan, Italy.
Ph.D Program in Molecular and Cellular Biology, Vita-Salute San Raffaele University, Milan, Italy.
Nat Metab. 2023 Mar;5(3):385-397. doi: 10.1038/s42255-023-00754-6. Epub 2023 Mar 6.
Depriving cells of nutrients triggers an energetic crisis, which is resolved by metabolic rewiring and organelle reorganization. Primary cilia are microtubule-based organelles at the cell surface, capable of integrating multiple metabolic and signalling cues, but their precise sensory function is not fully understood. Here we show that primary cilia respond to nutrient availability and adjust their length via glutamine-mediated anaplerosis facilitated by asparagine synthetase (ASNS). Nutrient deprivation causes cilia elongation, mediated by reduced mitochondrial function, ATP availability and AMPK activation independently of mTORC1. Of note, glutamine removal and replenishment is necessary and sufficient to induce ciliary elongation or retraction, respectively, under nutrient stress conditions both in vivo and in vitro by restoring mitochondrial anaplerosis via ASNS-dependent glutamate generation. Ift88-mutant cells lacking cilia show reduced glutamine-dependent mitochondrial anaplerosis during metabolic stress, due to reduced expression and activity of ASNS at the base of cilia. Our data indicate a role for cilia in responding to, and possibly sensing, cellular glutamine levels via ASNS during metabolic stress.
剥夺细胞营养会引发能量危机，这可以通过代谢重连和细胞器重组来解决。初级纤毛是细胞表面的基于微管的细胞器，能够整合多种代谢和信号线索，但它们的确切感觉功能尚未完全理解。在这里，我们表明初级纤毛对营养物质的可用性作出反应，并通过天冬酰胺合成酶 (ASNS) 介导的谷氨酰胺介导的氨酰化作用来调节其长度。营养物质剥夺会导致纤毛伸长，这是由线粒体功能降低、ATP 可用性降低和 AMPK 激活介导的，而不依赖于 mTORC1。值得注意的是，在营养胁迫条件下，无论是在体内还是体外，谷氨酰胺的去除和补充都是必需且充分的，通过 ASNS 依赖性谷氨酸生成恢复线粒体氨酰化作用，可以分别诱导纤毛伸长或回缩。在代谢应激期间，缺乏纤毛的 Ift88 突变细胞显示出依赖于谷氨酰胺的线粒体氨酰化作用减少，这是由于纤毛底部的 ASNS 表达和活性降低所致。我们的数据表明，在代谢应激期间，纤毛通过 ASNS 对细胞内谷氨酰胺水平作出反应，并可能对其进行感知。
