Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, Wales, UK.
Am J Physiol Endocrinol Metab. 2012 Jun 1;302(11):E1329-42. doi: 10.1152/ajpendo.00525.2011. Epub 2012 Feb 21.
Amino acid availability is a rate-limiting factor in the regulation of protein synthesis. When amino acid supplies become restricted, mammalian cells employ homeostatic mechanisms to rapidly inhibit processes such as protein synthesis, which demands high levels of amino acids. Muscle cells in particular are subject to high protein turnover rates to maintain amino acid homeostasis. Mammalian target of rapamycin complex 1 (mTORC1) is an evolutionary conserved multiprotein complex that coordinates a network of signaling cascades and functions as a key mediator of protein translation, gene transcription, and autophagy. Signal transduction through mTORC1, which is centrally involved in muscle growth through enhanced protein translation, is governed by intracellular amino acid supply. The branched-chain amino acid leucine is critical for muscle growth and acts in part through activation of mTORC1. Recent research has revealed that mTORC1 signaling is coordinated primarily at the lysosomal membranes. This discovery has sparked a wealth of research in this field, revealing several different signaling molecules involved in transducing the amino acid signal to mTORC1, including the Rag GTPases, MAP4K3, and Vps34/ULK1. This review evaluates the current knowledge regarding cellular mechanisms that control and sense the intracellular amino acid pool. We discuss the role of leucine and mTORC1 in the regulation of amino acid transport via the system L and system A transporters such as LAT1 and SNAT2, as well as protein degradation via autophagic and proteasomal pathways. We also describe the complexities of energy homeostasis via AMPK and cell receptor-mediated growth signals that also converge on mTORC1. Leucine is a particularly potent regulator of protein turnover, to the extent where leucine stimulation alone is sufficient to stimulate mTORC1 signal transduction. The significance of leucine in this context is not yet known; however, recent advancements in this area will also be covered within this review.
氨基酸的可利用性是蛋白质合成调控的限速因素。当氨基酸供应受到限制时，哺乳动物细胞会利用体内平衡机制迅速抑制蛋白质合成等过程，因为蛋白质合成需要大量的氨基酸。特别是肌肉细胞，其蛋白质周转率很高，以维持氨基酸的体内平衡。哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）是一种进化上保守的多蛋白复合物，协调着一系列信号级联反应，并作为蛋白质翻译、基因转录和自噬的关键介质。mTORC1 的信号转导，通过增强蛋白质翻译促进肌肉生长，其中心受到细胞内氨基酸供应的调控。支链氨基酸亮氨酸对肌肉生长至关重要，部分作用机制是通过激活 mTORC1。最近的研究揭示了 mTORC1 信号主要在溶酶体膜上协调。这一发现激发了该领域的大量研究，揭示了几种不同的信号分子参与将氨基酸信号转导至 mTORC1，包括 Rag GTPases、MAP4K3 和 Vps34/ULK1。本文评价了控制和感知细胞内氨基酸池的细胞机制的现有知识。我们讨论了亮氨酸和 mTORC1 在通过系统 L 和系统 A 转运体（如 LAT1 和 SNAT2）调节氨基酸转运以及通过自噬和蛋白酶体途径调节蛋白降解中的作用，以及通过 AMPK 和细胞受体介导的生长信号对能量平衡的影响，这些信号也会汇聚到 mTORC1。亮氨酸是一种特别有效的蛋白质周转率调节剂，其刺激足以单独刺激 mTORC1 信号转导。亮氨酸在这种情况下的重要性尚不清楚；然而，这一领域的最新进展也将在本文中介绍。
