Amino acid sensing and activation of mechanistic target of rapamycin complex 1

2016 ◽  
Vol 19 (1) ◽  
pp. 67-73 ◽  
Author(s):  
Daniel J. Ham ◽  
Gordon S. Lynch ◽  
René Koopman
Keyword(s):  
Amino Acid ◽  
Target Of Rapamycin ◽  
Mechanistic Target Of Rapamycin ◽  
Amino Acid Sensing

scholarly journals Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Tetsuya Kimura ◽  
Shigeyuki Nada ◽  
Noriko Takegahara ◽  
Tatsusada Okuno ◽  
Satoshi Nojima ◽  
...  
Keyword(s):  
Amino Acid ◽  
Macrophage Activation ◽  
Adaptor Protein ◽  
M2 Macrophages ◽  
Downstream Target ◽  
Mechanistic Target Of Rapamycin ◽  
M2 Polarization ◽  
M1 Polarization ◽  
Amino Acid Sensing ◽  
M1 And M2 Macrophages

Abstract Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H+-ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism.

scholarly journals Amino acid sensing and mTOR regulation: inside or out?

2009 ◽  
Vol 37 (1) ◽  
pp. 248-252 ◽  
Author(s):  
Deborah C.I. Goberdhan ◽  
Margret H. Ögmundsdóttir ◽  
Shubana Kazi ◽  
Bruno Reynolds ◽  
Shivanthy M. Visvalingam ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Growth Factor ◽  
Environmental Conditions ◽  
Detection System ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Amino Acid Sensing ◽  
The Impact ◽  
Mtor Signalling

mTOR (mammalian target of rapamycin) plays a key role in determining how growth factor, nutrient and oxygen levels modulate intracellular events critical for the viability and growth of the cell. This is reflected in the impact of aberrant mTOR signalling on a number of major human diseases and has helped to drive research to understand how TOR (target of rapamycin) is itself regulated. While it is clear that amino acids can affect TOR signalling, how these molecules are sensed by TOR remains controversial, perhaps because cells use different mechanisms as environmental conditions change. Even the question of whether they have an effect inside the cell or at its surface remains unresolved. The present review summarizes current ideas and suggests ways in which some of the models proposed might be unified to produce an amino acid detection system that can adapt to environmental change.

scholarly journals Evidence for the presence in rainbow trout brain of amino acid-sensing systems involved in the control of food intake

2018 ◽  
Vol 314 (2) ◽  
pp. R201-R215 ◽  
Author(s):  
Sara Comesaña ◽  
Cristina Velasco ◽  
Rosa M. Ceinos ◽  
Marcos A. López-Patiño ◽  
Jesús M. Míguez ◽  
...  
Keyword(s):  
Rainbow Trout ◽  
Amino Acid ◽  
Food Intake ◽  
Glutamine Metabolism ◽  
Taste Receptors ◽  
General Control ◽  
Mechanistic Target Of Rapamycin ◽  
Sensing Systems ◽  
Branched Chain ◽  
Amino Acid Sensing

To assess the hypothesis of central amino acid-sensing systems involved in the control of food intake in fish, we carried out two experiments in rainbow trout. In the first one, we injected intracerebroventricularly two different branched-chain amino acids (BCAAs), leucine and valine, and assessed food intake up to 48 h later. Leucine decreased and valine increased food intake. In a second experiment, 6 h after similar intracerebroventricular treatment we determined changes in parameters related to putative amino acid-sensing systems. Different areas of rainbow trout brain present amino acid-sensing systems responding to leucine (hypothalamus and telencephalon) and valine (telencephalon), while other areas (midbrain and hindbrain) do not respond to these treatments. The decreased food intake observed in fish treated intracerebroventricularly with leucine could relate to changes in mRNA abundance of hypothalamic neuropeptides [proopiomelanocortin (POMC), cocaine- and amphetamine-related transcript (CART), neuropeptide Y (NPY), and agouti-related peptide (AgRP)]. These in turn could relate to amino acid-sensing systems present in the same area, related to BCAA and glutamine metabolism, as well as mechanistic target of rapamycin (mTOR), taste receptors, and general control nonderepressible 2 (GCN2) kinase signaling. The treatment with valine did not affect amino acid-sensing parameters in the hypothalamus. These responses are comparable to those characterized in mammals. However, clear differences arise when comparing rainbow trout and mammals, in particular with respect to the clear orexigenic effect of valine, which could relate to the finding that valine partially stimulated two amino acid-sensing systems in the telencephalon. Another novel result is the clear effect of leucine on telencephalon, in which amino acid-sensing systems, but not neuropeptides, were activated as in the hypothalamus.

scholarly journals The E3 ubiquitin ligase ZNRF2 is a substrate of mTORC1 and regulates its activation by amino acids

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Gerta Hoxhaj ◽  
Edward Caddye ◽  
Ayaz Najafov ◽  
Vanessa P Houde ◽  
Catherine Johnson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Protein Phosphatase ◽  
E3 Ubiquitin Ligase ◽  
Mechanistic Target Of Rapamycin ◽  
Rag Gtpases ◽  
Intracellular Amino Acid ◽  
Amino Acid Levels ◽  
Amino Acid Sensing

The mechanistic Target of Rapamycin complex 1 (mTORC1) senses intracellular amino acid levels through an intricate machinery, which includes the Rag GTPases, Ragulator and vacuolar ATPase (V-ATPase). The membrane-associated E3 ubiquitin ligase ZNRF2 is released into the cytosol upon its phosphorylation by Akt. In this study, we show that ZNRF2 interacts with mTOR on membranes, promoting the amino acid-stimulated translocation of mTORC1 to lysosomes and its activation in human cells. ZNRF2 also interacts with the V-ATPase and preserves lysosomal acidity. Moreover, knockdown of ZNRF2 decreases cell size and cell proliferation. Upon growth factor and amino acid stimulation, mTORC1 phosphorylates ZNRF2 on Ser145, and this phosphosite is dephosphorylated by protein phosphatase 6. Ser145 phosphorylation stimulates vesicle-to-cytosol translocation of ZNRF2 and forms a novel negative feedback on mTORC1. Our findings uncover ZNRF2 as a component of the amino acid sensing machinery that acts upstream of Rag-GTPases and the V-ATPase to activate mTORC1.

scholarly journals TREINAMENTO DE FORÇA/SOBRECARGA MECÂNICA E SINALIZAÇÃO DO COMPLEXO 1 DO ALVO DA RAPAMICINA EM MAMÍFEROS NA HIPERTROFIA MUSCULAR EM DIFERENTES MODELOS EXPERIMENTAIS: REVISÃO SISTEMÁTICA

2017 ◽  
Vol 25 (1) ◽  
pp. 168
Author(s):  
André Katayama Yamada ◽  
Vanessa Azevedo Voltarelli ◽  
Adriana Pertille ◽  
Carlos Roberto Bueno Júnior
Keyword(s):  
Skeletal Muscle ◽  
Amino Acid ◽  
Resistance Exercise ◽  
Strength Training ◽  
Muscle Hypertrophy ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Skeletal Muscle Hypertrophy ◽  
Mechanical Overload ◽  
Amino Acid Sensing

O objetivo deste artigo de revisão sistemática foi apresentar o envolvimento da sinalização de aminoácidos e mecanotransdução na ativação do complexo 1 do alvo da rapamicina em mamíferos (mTORC1) na musculatura esquelética de animais e a expressão e papel do mTORC1 em humanos submetidos ao treinamento de força/estímulo mecânico. Foi realizada uma busca na base de dados PubMed com as seguintes palavras-chave: mTORC1, mammalian target of rapamycin complex 1, resistance exercise, strength training, mechanical overload e skeletal muscle hypertrophy, amino acid sensing transporter e mechanotransduction. Evidências demonstram que a ativação do mTORC1 possui correlação positiva com a hipertrofia muscular induzida pelo treinamento de força/estímulo mecânico. O mTORC1 integra diversos sinais oriundos de aminoácidos (sinalização de transportadores e sensores) e estímulo mecânico/treinamento de força (mecanotransdução). Ademais, o emprego de modelos de camundongos mutantes, abordagens genéticas, farmacológicas, cultura de células, modelos experimentais de treinamento de força para animais, assim como estudos com humanos, vêm possibilitando a elucidação destes mecanismos moleculares.

scholarly journals Crystal structure of arginine-bound lysosomal transporter SLC38A9 in the cytosol-open state

2018 ◽  
Author(s):  
Hsiang-Ting Lei ◽  
Jinming Ma ◽  
Silvia Sanchez Martinez ◽  
Tamir Gonen
Keyword(s):  
Crystal Structure ◽  
Amino Acid ◽  
Signaling Pathway ◽  
Transmembrane Helix ◽  
Underlying Mechanism ◽  
Transitional State ◽  
Mechanistic Target Of Rapamycin ◽  
Mtorc1 Signaling ◽  
Solute Carrier ◽  
Amino Acid Sensing

Amino acid-dependent activation of mechanistic target of rapamycin complex 1 (mTORC1) is essential to reflect nutrient availabilities in cells for cell growth and metabolism1. Solute carrier 38 family A member 9 (SLC38A9) is the lysosomal transporter responsible for amino acid sensing in the mTORC1 signaling pathway2–4. Here we present the first crystal structure of SLC38A9 from Danio rerio in complex with arginine. As captured in the cytosol-open state, the bound arginine was locked in a transitional state stabilized by the transmembrane helix 1 (TM1) of SLC38A9 which was anchored at the grove between transmembrane helix 5 and 7 inside the transporter. The key motif WNTMM on TM1, contributing to the anchoring interactions, is highly conserved in various species. Mutations in WNTMM motif abolished arginine transport by SLC38A9. The underlying mechanism of substrate binding is critical for both sensitizing mTORC1 signaling pathway to amino acids and for maintaining amino acid homeostasis across lysosomal membranes2.

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