mTOR gets greasy: lysosomal sensing of cholesterol.
mTOR gets greasy: lysosomal sensing of cholesterol.
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mTOR 变得油腻：溶酶体对胆固醇的感知。
DOI：
10.1038/s41422-022-00740-9
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发表时间：
2023
期刊：
影响因子：
44.1
通讯作者：
Lamming,DudleyW
中科院分区：
文献类型：
--
作者：
Bar-Peled,Liron;Lamming,DudleyW
雷帕霉素复合物1（mTORC 1）的机制靶点调节多种代谢过程，以响应营养刺激和环境线索。在最近一期的《科学》杂志中，Shin等人报道了一种溶酶体G蛋白偶联受体样蛋白的鉴定，该蛋白与胆固醇结合，并将这种关键的常量营养素的可用性与mTORC 1活化偶联。雷帕霉素的机制靶点（mTOR）是一种进化上保守的丝氨酸/苏氨酸蛋白激酶，一种小分子，大约50年前在复活节岛采集的样本中发现。在过去的二十年中，已经清楚的是，mTOR，特别是mTOR复合物1（mTORC 1），在基本的细胞过程和代谢中起着核心作用，作为信号节点整合细胞营养和激素信号，以适当地协调合成代谢和分解代谢过程与营养物质的可用性。mTORC 1的一些最佳表征底物包括S6 K1、4 EBP 1和ULK 1，mTORC 1通过这些底物调节蛋白质翻译、核糖体生物合成、脂肪生成、核苷酸合成和自噬等过程。mTORC 1激酶活性通过控制其与溶酶体表面的小GTdR heb的相互作用来调节。通过特定营养物质（特别是氨基酸）的可用性将mTORC 1募集到溶酶体表面的过程在其他地方有详细描述。2简单地说，mTORC 1被小GTP酶的Rag家族的异二聚体复合物募集到溶酶体表面;当这些Rag蛋白以特定构型装载GTP或GDP时，它们将mTORC 1定位到溶酶体表面。Rag GTP酶的核苷酸负载状态由GTP酶激活蛋白（GAP）和鸟嘌呤核苷酸交换因子（GEF）控制。特别相关的是，GATOR 1复合物作为RagA和RagB的GAP起作用，而第二种复合物GATOR 2通过未知的机制抑制GATOR 1 GAP活性。3如图1所示，氨基酸（包括亮氨酸和精氨酸）和甲硫氨酸代谢物SAM的特异性营养素传感器通过结合GATOR 2（例如，Sestrin 1/2/3和CASTOR 1/2）或GATOR 1（SAMTOR）并抑制其活性而起作用。糖酵解中间体DHAP的未知传感器也通过GATOR 1向mTORC 1发出信号。其他氨基酸的传感涉及低亲和力溶酶体氨基酸转运蛋白SLC 38 A9，其可以通过Ragulator向mTORC 1发送信号，Ragulator对RagA/RagB具有GEF活性。如果mTORC 1活性表明了合成代谢过程所需的营养物质的可用性，并作为大分子合成的基石，我们可能会认为mTORC 1
The mechanistic Target of Rapamycin Complex 1 (mTORC1) regulates diverse metabolic processes in response to nutrient stimuli and environmental cues. In a recent issue of Science, Shin et al. report the identification of a lysosomal G proteincoupled receptor-like protein that binds to cholesterol and couples the availability of this critical macronutrient to mTORC1 activation.The mechanistic Target of Rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase that is inhibited by rapamycin, a small molecule discovered in samples collected on Easter Island almost 50 years ago. Over the past two decades, it has become clear that mTOR, in particular, mTOR complex 1 (mTORC1), plays a central role in essential cellular processes and metabolism, functioning as a signaling node to integrate cellular nutrient and hormonal cues to appropriately coordinate anabolic and catabolic processes with the availability of nutrients. 1 Some of the best characterized substrates of mTORC1 include S6K1, 4EBP1, and ULK1, through which mTORC1 regulates processes including protein translation, ribosome biogenesis, lipogenesis, nucleotide synthesis, and autophagy. mTORC1 kinase activity is regulated through control of its interaction with the small GTPase Rheb at the lysosomal surface. The recruitment of mTORC1 to the lysosomal surface by the availability of specific nutrients, particularly amino acids, is described in detail elsewhere. 2 Briefly, mTORC1 is recruited to the lysosomal surface by heterodimeric complexes of the Rag family of small GTPases; when these Rag proteins are loaded with GTP or GDP in a specific configuration, they localize mTORC1 to the lysosomal surface. The nucleotide loading state of the Rag GTPases is controlled by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Of particular relevance, the GATOR1 complex functions as a GAP for RagA and RagB, while a second complex, GATOR2, acts to inhibit GATOR1 GAP activity via unknown mechanisms. 3 As shown in Fig. 1, specific nutrient sensors for amino acids including leucine and arginine and the methionine metabolite SAM act by binding to and inhibiting the activity of either GATOR2 (eg, Sestrin1/2/3 and CASTOR1/2) or GATOR1 (SAMTOR). An unknown sensor of the glycolysis intermediate DHAP also signals to mTORC1 via GATOR1. The sensing of other amino acids involves a low-affinity lysosomal amino acid transporter, SLC38A9, which may signal to mTORC1 via the Ragulator, which has GEF activity toward RagA/RagB. If mTORC1 activity indicates the availability of nutrients required to fuel anabolic processes and serve as building blocks for macromolecule synthesis, we might expect that mTORC1