Cholesterol Sensing The mTORC1 kinase is a master nutrient sensor that governs cellular metabolism. When dysregulated, this kinase drives several human diseases, including cancer and diabetes. Recent work has delineated a pathway through which amino acids regulate mTORC1. In contrast, little is known about how sterols may affect mTORC1 signaling. Castellano et al. provide detailed mechanistic evidence for how cholesterol, derived from the processing of low-density lipoprotein in the lysosomal lumen, drives mTORC1 signaling. They identify the key players that couple lysosomal cholesterol levels to mTORC1 activation. Unexpectedly, the putative amino acid transporter SLC38A9, which is implicated in mTORC1 regulation by arginine, is essential for mTORC1 activation by cholesterol. Furthermore, the authors uncover a physical and functional interaction between SLC38A9 and the major lysosomal cholesterol transporter, Niemann-Pick C1 (NPC1) protein. The SLC38A9-NPC1 complex is key to the ability of mTORC1 to respond to variations in dietary lipid supply. Science , this issue p. [1306][1] [1]: /lookup/doi/10.1126/science.aag1417

中文翻译：

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溶酶体胆固醇激活 mTORC1

胆固醇感应 mTORC1 激酶是控制细胞代谢的主要营养传感器。当失调时，这种激酶会导致多种人类疾病，包括癌症和糖尿病。最近的工作描绘了氨基酸调节 mTORC1 的途径。相比之下，关于甾醇如何影响 mTORC1 信号传导知之甚少。卡斯特拉诺等人。提供详细的机制证据，说明源自溶酶体腔中低密度脂蛋白加工的胆固醇如何驱动 mTORC1 信号传导。他们确定了将溶酶体胆固醇水平与 mTORC1 激活相结合的关键因素。出乎意料的是，推测的氨基酸转运蛋白 SLC38A9 与精氨酸对 mTORC1 的调节有关，对胆固醇激活 mTORC1 至关重要。此外，作者揭示了 SLC38A9 与主要溶酶体胆固醇转运蛋白 Niemann-Pick C1 (NPC1) 蛋白之间的物理和功能相互作用。SLC38A9-NPC1 复合物是 mTORC1 响应膳食脂质供应变​​化能力的关键。科学，这个问题 p。[1306][1][1]：/lookup/doi/10.1126/science.aag1417