氨基酸调节哺乳动物雷帕霉素靶蛋白复合体1信号通路的分子机制

哺乳动物雷帕霉素靶蛋白复合体1(mTORC1)信号通路能够感受一系列细胞内外环境因素的变化,如氨基酸浓度、能量水平、生长因子等进而调节细胞生长。氨基酸不仅是合成蛋白质的底物,也可作为信号分子激活mTORC1信号通路,促进蛋白质合成。溶酶体是氨基酸激活mTORC1信号通路过程中一个重要细胞器,mTORC1感应氨基酸的上游信号通路需要溶酶体相关蛋白及胞浆蛋白的参与完成。本文综述了氨基酸调节mTORC1信号通路的分子机制,为营养因子调控蛋白质合成的关键通路提供参考。

氨基酸调节mTORC1信号通路的研究进展

氨基酸是合成蛋白质的底物,也可作为信号分子激活哺乳动物雷帕霉素靶蛋白复合体1(mTORC1)。氨基酸调控mTORC1活性的关键步骤是将mTORC1定位于溶酶体表面,Rag GTPase、Ragulator、v-ATPase和SLC38A9等溶酶体相关蛋白及GATOR、Sestrins等胞质蛋白在其中发挥重要的作用。

Mechanisms mediating the effects of alcohol and HIV anti-retroviral agents on mTORC1,mTORC2 and protein synthesis in myocytes

Alcoholism and acquired immune deficiency syndrome are associated with severe muscle wasting.This impairment in nitrogen balance arises from increased protein degradation and a decreased rate of protein synthesis.The regulation of protein synthesis is a complex process involving alterations in the phosphorylation state and protein-protein interaction of various components of the translation machinery and mammalian target of rapamycin(mTOR) complexes.This review describes mechanisms that regulate protein synthesis in cultured C2C12 myocytes following exposure to either alcohol or human immunodeficiency virus antiretroviral drugs.Particular attention is given to the upstream regulators of mTOR complexes and the downstream targets which play an important role in translation.Gaining a better understanding of these molecular mechanisms could have important implications for preventing changes in lean body mass in patients with catabolic conditions or illnesses.

Signal integration in the （m）TORC1 growth pathway

BACKGROUND： The protein kinase Target Of Rapamycin （TOR） is a nexus for the regulation of eukaryotic cell growth. TOR assembles into one of two distinct signalling complexes, TOR complex 1 （TORC1） and TORC2 （mTORC1/2 in mammals）, with a set of largely non-overlapping protein partners. （m）TORC 1 activation occurs in response to a series of stimuli relevant to cell growth, including nutrient availability, growth factor signals and stress, and regulates much of the cell＇s biosynthetic activity, from proteins to lipids, and recycling through autophagy, mTORC1 regulation is of great therapeutic significance, since in humans many of these signalling complexes, alongside subunits of mTORC1 itself, are implicated in a wide variety of pathophysiologies, including multiple types of cancer, neurological disorders, neurodegenerative diseases and metabolic disorders including diabetes. METHODOLOGY： Recent years have seen numerous structures determined of （m）TOR, which have provided mechanistic insight into （m）TORC 1 activation in particular, however the integration of cellular signals occurs upstream of the kinase and remains incompletely understood. Here we have collected and analysed in detail as many as possible of the molecular and structural studies which have shed light on （m）TORC 1 repression, activation and signal integration. CONCLUSIONS： A molecular understanding of this signal integration pathway is required to understand how （m）TORC1 activation is reconciled with the many diverse and contradictory stimuli affecting cell growth. We discuss the current level of molecular understanding of the upstream components of the （m）TORC1 signalling pathway, recent progress on this key biochemical frontier, and the future studies necessary to establish a mechanistic understanding of this master-switch for eukaryotic cell growth.

Sensors for the mTORC1 pathway regulated by amino acids

The mechanistic target of rapamycin complex 1(mTORC1)controls cell growth and metabolism in response to various environmental inputs,especially amino acids.In fact,the activity of mTORC1 is highly sensitive to changes in amino acid levels.Over past decades,a variety of proteins have been identified as participating in the mTORC1 pathway regulated by amino acids.Classically,the Rag guanosine triphosphatases(GTPases),which reside on the lysosome,transmit amino acid availability to the mTORC1 pathway and recruit mTORC1 to the lysosome upon amino acid sufficiency.Recently,several sensors of leucine,arginine,and S-adenosylmethionine for the amino acidstimulated mTORC1 pathway have been coming to light.Characterization of these sensors is requisite for understanding how cells adjust amino acid sensing pathways to their different needs.In this review,we summarize recent advances in amino acid sensing mechanisms that regulate mTORC1 activity and highlight these identified sensors that accurately transmit specific amino acid signals to the mTORC1 pathway.

mTORC1通路中氨基酸信号转导相关机制研究进展

雷帕霉素靶点蛋白(target of rapamycin,TOR)作为细胞内重要的生长和代谢调节中枢,主要通过形成两种复合物TORC1与TORC2发挥其功能。其中TORC1接收广泛的细胞内信号,如氨基酸水平、生长因子、能量以及缺氧状态等,通过调控蛋白质合成来促进细胞的增殖与生长。在这些信号当中,氨基酸不仅能够激活TORC1通路,还同时作为其他信号激活TORC1的必需条件。目前,对于生长因子和能量水平激活TORC1过程的分子机制已有较深入的认识,而对于氨基酸信号如何转导至TORC1的分子机制直到近年来才有了新的突破。该文通过梳理已发表的哺乳动物细胞中氨基酸信号调控mTORC1分子机制的相关实验结论,对该领域的研究方向进行了总结和展望。