mTORC1信号通路调控细胞自噬的研究进展

蛋白激酶mTORC1主要感应细胞内的营养状态和细胞外的压力刺激,通过磷酸化众多下游底物蛋白,参与调控细胞的生长、增殖和代谢等过程.近年来的研究表明, m TORC1信号通路在细胞内的重要分解代谢过程——细胞自噬的调控中发挥主导作用.在细胞自噬过程的不同阶段发挥作用的多个蛋白陆续被鉴定为mTORC1的直接磷酸化底物,表明mTORC1在细胞自噬过程的不同阶段均发挥调控作用.以上作用机制让mTORC1精确而全面地控制细胞自噬的起始、终止和强度,进而帮助细胞更好地应对细胞内外环境的改变.本文将围绕mTORC1信号通路在细胞自噬调控中的主导作用综述近年来的相关研究进展.     

mTORC1在慢性肾功能不全胰岛素抵抗中的作用

代谢综合征(MetS)在慢性肾功能不全(CKD)患者中普遍存在,与CKD预后密切相关。胰岛素抵抗(IR)作为MetS的基础,是非糖尿病CKD患者疾病进展的独立危险因素。而mTORC1信号通路可感受多种环境变化调节机体的生长代谢稳态,参与肿瘤、肥胖、2型糖尿病等多种疾病发生发展过程。mTORC1过度激活被认为是2型糖尿病IR的机制之一,但在CKD疾病状态下,mTORC1与IR的关系尚不十分清楚。本文就CKD疾病状下,mTORC1对胰岛素信号通路的影响,做一简要概述,为CKD患者IR的治疗提供参考。     

钠离子依赖的中性氨基酸转运蛋白SNAT2的研究进展

钠离子依赖的中性氨基酸转运蛋白2 (sodium-coupled neutral amino acid transporter 2,SNAT2)是SLC38基因编码家族中转运系统A (SystemA)的重要成员。SNAT2广泛表达于哺乳动物各组织中。其表达受高渗、pH值、激素、炎症因子等因素的影响。SNAT2可以通过改变细胞内氨基酸的水平来调控哺乳动物雷帕霉素靶蛋白复合物1(mammalian target of rapamycin complex 1,mTORC1)的下游通路,从而影响细胞蛋白质合成。SNAT2在肥胖、糖尿病、关节炎、癌症等多种病理生理过程中发挥着重要的作用。本文对SNAT2的研究进展进行综述。     

氨基酸调节mTORC1信号通路的分子机制

正哺乳动物雷帕霉素靶蛋白(mTOR)是存在于哺乳动物体内的一种高度保守的丝氨酸/苏氨酸蛋白激酶,能够调节细胞内多种物质的代谢。它参与组成哺乳动物雷帕霉素靶蛋白复合体1(mTORC1)和哺乳动物雷帕霉素靶蛋白复合体2(mTORC2)2种复合体。在2015年发现的人类mT ORC1结构基础上,Saxton等人揭示了亮氨酸对于mT ORC1通路复杂的调控机制。他     

胰岛素信号转导通路和衰老研究进展

衰老是生物学中一个基本的、尚未解决的问题。过去十几年在无脊椎动物方面的研究表明,胰岛素/胰岛素样生长因子信号通路发生改变可以增加寿命和延迟衰老。在酵母、线虫、果蝇和小鼠等方面的研究已经勾画出了这个神秘问题的大致轮廓。     

痕量胺相关受体1信号转导通路的研究进展

痕量胺相关受体1 (trace amine-associated receptor 1, TAAR1)是一类经典G蛋白耦联受体,广泛分布于哺乳动物的脑内,尤其是边缘系统和富集单胺能神经元的区域,是一种在所有物种中高度保守的TAAR亚型。TAAR1可以特异性应答中枢神经系统和外周组织中的内源性微量胺,在单胺系统和谷氨酸系统失调引发的精神障碍的病理生理学机制中具有重要意义。另外,TAAR1调节剂可以作用于内向整流钾离子通道,对突触传递和神经元活动具有调节作用。最新的研究表明,TAAR1通过调节细胞内信号通路和底物磷酸化发挥一系列生理功能,与情绪、认知、恐惧和成瘾有着密切的联系。本综述对TAAR1信号转导通路的相关研究进行了详细的梳理,旨在揭示TAAR1作为神经精神疾病药物治疗新靶点的巨大潜力。     

RhoA—p38MAPK信号转导通路及其进展

RhoA属于小G蛋白家族成员,p38MAPK属于丝/苏氨酸蛋白激酶家族成员。本文从巨噬细胞、肌肉细胞、成纤维细胞、神经元和肿瘤几个方面阐述RhoA-p38MAPK信号通路的研究进展,此信号通路在细胞骨架的改变和肿瘤的发生发展方面有望成为新的研究热点。     

中枢白细胞介素-1系统及信号转导研究进展

中枢白细胞介素 1(centralinterleukin 1,IL 1)以及功能和结构相关的分子已构成相对独立的中枢IL 1系统 (IL 1system)。IL 1系统的研究不断深入 ,新成员及其功能不断被发现 ,极大地扩展了该系统新老成员的生物学作用、信号转导通路 ,以及相互之间的联系。本文总结了近几年关于中枢IL 1系统的研究进展 ,包括IL 1系统新成员、信号转导通路和新的信号分子 ,以及IL 1系统与某些生理过程或病理生理过程的关系。     

Nephrin 信号转导机制研究进展

Nephrin作为肾小球足细胞膜上的跨膜蛋白,是足细胞裂隙膜重要的结构分子。近来发现,nephrin分子细胞内段的酪氨酸残基在被酪氨酸激酶fyn（属Src激酶家族成员）磷酸化后,能激活下游信号分子,形成足细胞内特有的信号转导通路,如nephrin—podocin—MAPK—AP-1、nephrin—CD2AP-P13K-Akt／PKB、nephrin-Nck—Rac／CDC42等。这些信号通路参与了足细胞胚胎发生、细胞生存与细胞骨架重组等许多重要生理病理过程的调节。同样,nephrin蛋白及mRNA的表达也受许多因素的调节。研究nephrin及其信号转导机制对了解并防治肾小球硬化有重要意义。     

内皮细胞血管紧张素Ⅱ信号转导通路的研究进展

血管紧张素Ⅱ(Ang Ⅱ)不仅发挥着收缩血管和调节血压的功能,还参与炎症、内皮细胞功能障碍、动脉粥样硬化、高血压和充血性心衰的发生与发展.Ang Ⅱ通过AT1受体,激活内皮细胞MAPK、NADPH和ROS、非受体酪氨酸激酶及受体酪氨酸激酶通路产生各种生物学效应,参与内皮细胞功能调节,引发内皮细胞功能障碍和血管的炎症反应.     

Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation

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Mechanisms involved in the coordinate regulation of mTORC1 by insulin and amino acids

In this study, we explored the coordinate regulation of mTORC1 by insulin and amino acids. Rat livers were perfused with medium containing various concentrations of insulin and/or amino acids. At fasting (1×) or 2× (2×AA) concentrations of amino acids, insulin maximally stimulated Akt phosphorylation but had no effect on global rates of protein synthesis. In the absence of insulin, 4×AA produced a moderate stimulation of protein synthesis and activation of mTORC1. The combination of 4×AA and insulin produced a maximal stimulation of protein synthesis and activation of mTORC1. These effects were accompanied by decreases in raptor and PRAS40 and an increase in RagC associated with mTOR (mammalian target of rapamycin). The studies were extended to a cell culture model in which mTORC1 activity was repressed by deprivation of leucine and serum, and resupplementation with the amino acid and insulin acted in an additive manner to restore mTORC1 activation. In deprived cells, mTORC1 was activated by expressing either constitutively active (ca) Rheb or a caRagB·caRagC complex, and coexpression of the constructs had an additive effect. Notably, resupplementation with leucine in cells expressing caRheb or with insulin in cells expressing the caRagB·caRagC complex was as effective as resupplementation with both leucine and insulin in non-transfected cells. Moreover, changes in mTORC1 activity correlated directly with altered association of mTOR with RagB/RagC, Rheb, raptor, and PRAS40. Overall, the results suggest that amino acids signal through the Rag complex and insulin through Rheb to achieve coordinate activation of mTORC1.     

Multiple amino acid sensing inputs to mTORC1

The evolutionarily conserved target of rapamycin complex 1 (TORC1) is a master regulator of cell growth and metabolism. In mammals, growth factors and cellular energy stimulate mTORC1 activity through inhibition of the TSC complex (TSC1-TSC2-TBC1D7), a negative regulator of mTORC1. Amino acids signal to mTORC1 independently of the TSC complex. Here, we review recently identified regulators that link amino acid sufficiency to mTORC1 activity and how mutations affecting these regulators cause human disease.     

Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1

The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and amino acids, which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of amino acids by canonical autophagy or proteasomal degradation but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach.     

The Rag GTPase-Ragulator complex attenuates TOR complex 1 signaling in fission yeast

Target of rapamycin complex 1 (TORC1) is an evolutionarily conserved protein kinase complex, whose activation in response to nutrients suppresses autophagy. In mammalian cells, amino-acid stimuli induce lysosomal translocation and activation of MTORC1 through the RRAG GTPase heterodimer, which is tethered to the surface of lysosomes by the Ragulator complex. Our recent study demonstrated that the fission yeast Schizosaccharomyces pombe also has a Ragulator complex that anchors the Gtr1-Gtr2 Rag GTPase heterodimer to the vacuole, a lysosome-like organelle. Unexpectedly, however, neither vacuolar localization nor activation of TORC1 is dependent on the Rag-Ragulator complex, which instead plays a critical role in attenuating TORC1 signaling. Our findings suggest dual functionality of the Rag GTPase in both activation and inactivation of TORC1.     

磷酸化与泛素化修饰对雷帕霉素靶蛋白复合物1(TORC1)信号通路的调控

TORC1是一个在真核生物中高度保守的激酶复合物,能通过感应营养物质、生长因子、能量水平等信号调节细胞代谢水平和生长。TORC1信号通路的失调与代谢紊乱、神经病变、癌症和衰老密切相关。本文比较了酵母细胞及哺乳动物细胞中TORC1的结构与功能,并着重综述了磷酸化和泛素化修饰在TORC1信号通路中的作用。由于磷酸化和泛素化在传导外界信号至TORC1以及调节TORC1下游通路中均发挥重要作用,因此深入研究磷酸化和泛素化对TORC1信号通路的影响,将为药物靶点的发现提供新思路。     

Orexin/Hypocretin Activates mTOR Complex 1 (mTORC1) via an Erk/Akt-independent and Calcium-stimulated Lysosome v-ATPase Pathway

The lack of the neuropeptide orexin, also known as hypocretin, results in narcolepsy, a chronic sleep disorder characterized by frequent sleep/cataplexy attacks and rapid eye movement sleep abnormalities. However, the downstream pathways of orexin signaling are not clearly understood. Here, we show that orexin activates the mTOR pathway, a central regulator of cell growth and metabolism, in the mouse brain and multiple recombinant cell lines that express the G protein-coupled receptors (GPCRs), orexin 1 receptor (OX1R) or orexin 2 receptor (OX2R). This orexin/GPCR-stimulated mTOR activation is sensitive to rapamycin, an inhibitor of mTOR complex 1 (mTORC1) but is independent of two well known mTORC1 activators, Erk and Akt. Rather, our studies indicate that orexin activates mTORC1 via extracellular calcium influx and the lysosome pathway involving v-ATPase and Rag GTPases. Moreover, a cytoplasmic calcium transient is sufficient to mimic orexin/GPCR signaling to mTORC1 activation in a v-ATPase-dependent manner. Together, our studies suggest that the mTORC1 pathway functions downstream of orexin/GPCR signaling, which plays a crucial role in many physiological and metabolic processes.     

High mTORC1 signaling is maintained,while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state

This study investigated age-associated changes to protein synthesis and degradation pathways in the quadriceps muscles of male C57BL/6J mice at 5 ages, between 4 and 24 months (m). Sarcopenia was evident by 18 m and was accompanied by hyper-phosphorylation of S6K1, indicating increased mTORC1 signaling. Proteasomal and autophagosomal degradation pathways were also impacted by aging. In the 1% NP40 insoluble protein fraction, the abundance of MuRF1 increased at 24 m, while p62 increased at 15 m, and remained elevated at older ages. In addition, we investigated how protein synthesis and degradation pathways are modulated by fasting in young (4 m) and old (24 m) muscles, and showed that old mice respond to fasting less robustly compared with young. Overnight fasting for 16 h caused de-phosphorylation of AKT and molecules downstream of mTORC1 (S6K1, rpS6 and 4E-BP1) in young, but not old muscles. A longer time of fasting (24 h) was required to reduce phosphorylation of these molecules in old mice. Induction of MuRF1 and Fbxo32 mRNA was also more robust in young compared with old muscles following fasting for 16 h. In addition, a 16 h fast reduced ULK1 phosphorylation at the mTORC1 specific site Ser757 only in young muscles. The striking accumulation of insoluble p62 protein in muscles of all old male mice (fed or fasted), suggests age-related dysregulation of autophagy and protein aggregation. These data provide an insight into the mechanisms of metabolic responses that affect protein homeostasis in old skeletal muscles, with applications to design of clinical interventions that target sarcopenia.