The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that responds to a diverse set of environmental inputs, including amino acids. Over the past 10 years, a ...number of proteins have been identified that help transmit amino acid availability to mTORC1. However, amino acid sensors for this pathway have only recently been discovered. Here, we review these recent advances and highlight the variety of unexplored questions that emerge from the identification of these sensors.
Wolfson and Sabatini describe recent advances in understanding how amino acids are sensed upstream of mTORC1, in particular detailing the discovery of the first amino acid sensors for the pathway. In addition, they analyze how components of the mTORC1 pathway, including the amino acid sensors, are conserved across evolution.
Magnetic and inertial measurement units are an emerging technology to obtain 3D orientation of body segments in human movement analysis. In this respect, sensor fusion is used to limit the drift ...errors resulting from the gyroscope data integration by exploiting accelerometer and magnetic aiding sensors. The present study aims at investigating the effectiveness of sensor fusion methods under different experimental conditions. Manual and locomotion tasks, differing in time duration, measurement volume, presence/absence of static phases, and out-of-plane movements, were performed by six subjects, and recorded by one unit located on the forearm or the lower trunk, respectively. Two sensor fusion methods, representative of the stochastic (Extended Kalman Filter) and complementary (Non-linear observer) filtering, were selected, and their accuracy was assessed in terms of attitude (pitch and roll angles) and heading (yaw angle) errors using stereophotogrammetric data as a reference. The sensor fusion approaches provided significantly more accurate results than gyroscope data integration. Accuracy improved mostly for heading and when the movement exhibited stationary phases, evenly distributed 3D rotations, it occurred in a small volume, and its duration was greater than approximately 20 s. These results were independent from the specific sensor fusion method used. Practice guidelines for improving the outcome accuracy are provided.
The mechanistic (or mammalian) target of rapamycin (mTOR) is a kinase that regulates key cellular functions linked to the promotion of cell growth and metabolism. This kinase, which is part of two ...protein complexes termed mTOR complex 1 (mTORC1) and 2 (mTORC2), has a fundamental role in coordinating anabolic and catabolic processes in response to growth factors and nutrients. Of the two mTOR complexes, mTORC1 is by far the best characterized. When active, mTORC1 triggers cell growth and proliferation by promoting protein synthesis, lipid biogenesis, and metabolism, and by reducing autophagy. The fact that mTORC1 deregulation is associated with several human diseases, such as type 2 diabetes, cancer, obesity and neurodegeneration, highlights its importance in the maintenance of cellular homeostasis. Over the last years, several groups observed that mTORC1 inhibition, in addition to reducing protein synthesis, deeply affects gene transcription. Here, we review the connections between mTORC1 and gene transcription by focusing on its impact in regulating the activation of specific transcription factors including including STAT3, SREBPs, PPARγ, PPARα, HIF1α, YY1–PGC1α and TFEB. We also discuss the importance of these transcription factors in mediating the effects of mTORC1 on various cellular processes in physiological and pathological contexts.
The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well understood why pyruvate ...supplementation allows cells lacking ETC function to proliferate. We used a CRISPR-based genetic screen to identify genes whose loss sensitizes human cells to phenformin, a complex I inhibitor. The screen yielded GOT1, the cytosolic aspartate aminotransferase, loss of which kills cells upon ETC inhibition. GOT1 normally consumes aspartate to transfer electrons into mitochondria, but, upon ETC inhibition, it reverses to generate aspartate in the cytosol, which partially compensates for the loss of mitochondrial aspartate synthesis. Pyruvate stimulates aspartate synthesis in a GOT1-dependent fashion, which is required for pyruvate to rescue proliferation of cells with ETC dysfunction. Aspartate supplementation or overexpression of an aspartate transporter allows cells without ETC activity to proliferate. Thus, enabling aspartate synthesis is an essential role of the ETC in cell proliferation.
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•A CRISPR-Cas9 genetic screen reveals that GOT1 loss kills cells upon ETC inhibition•In cells with ETC inhibition, GOT1 reverses flux to generate aspartate in the cytosol•Aspartate is limiting for proliferation in cells with ETC inhibition•Pyruvate reverses the effects of ETC inhibition by inducing aspartate synthesis
Aspartate is a limiting metabolite for proliferation in cells with mitochondrial electron transport chain defects.
The mTOR Complex 1 (mTORC1) pathway regulates cell growth in response to numerous cues, including amino acids, which promote mTORC1 translocation to the lysosomal surface, its site of activation. The ...heterodimeric RagA/B-RagC/D GTPases, the Ragulator complex that tethers the Rags to the lysosome, and the v-ATPase form a signaling system that is necessary for amino acid sensing by mTORC1. Amino acids stimulate the binding of guanosine triphosphate to RagA and RagB but the factors that regulate Rag nucleotide loading are unknown. Here, we identify HBXIP and C7orf59 as two additional Ragulator components that are required for mTORC1 activation by amino acids. The expanded Ragulator has nucleotide exchange activity toward RagA and RagB and interacts with the Rag heterodimers in an amino acid- and v-ATPase-dependent fashion. Thus, we provide mechanistic insight into how mTORC1 senses amino acids by identifying Ragulator as a guanine nucleotide exchange factor (GEF) for the Rag GTPases.
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► C7orf59 and HBXIP are required for amino acid sensing by the mTORC1 pathway ► C7orf59 and HBXIP are additional components the Ragulator complex ► Ragulator is a GEF for the RagA and RagB GTPases ► The v-ATPase controls Ragulator function in cells in response to amino acids
Identification of two additional subunits of the Ragulator complex reveals intrinsic GEF activity, explaining how Ragulator activates the Rag GTPases that, in turn, activate the mTORC1 pathway.
ITALIANO: E' stata effettuata un'indagine preliminare sullo stato di micorrizazione di piante di Abies alba e Fagus sylvatica in due stazioni toscane, Vallombrosa e Pian di Novello. Sono state ...definite 10 forme ectomicorriziche, ben distinguibili per caratteri macroscopici, di cui otto comuni ad entrambe le specie e le stazioni esaminate. Fra le due stazioni sono state riscontrate ridotte differenze nella percentuale di micorrizazione, mentre la presenza delle diverse forme all'interno della stessa specie e' risultata assai variabile. L'eterogeneita' dei dati raccolti suggerisce l'esigenza di ulteriori indagini correlate alle differenze microstazionali.
A preliminar investigation on the mycorrhizal status of Abies alba and Fagus sylvatica was carried out in two Tuscan sites, Vallombrosa and Pian di Novello. Only ten different mycorrhizal types were recognized; eight of them were found on both the two species and sites. Little differences were found in the total percentage of mycorrhizas between the two sites, while there was variability in the presence of the same types in samples of the same species. Data suggest the need of further investigation on the relationship between microsites and mycorrhizas.
The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form heterodimers ...consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. The Rag heterodimer uses a unique “locking” mechanism to stabilize its active (GTPRagA–RagCGDP) or inactive (GDPRagA–RagCGTP) nucleotide states. The Ragulator complex tethers the Rag heterodimer to the lysosomal surface, and the SLC38A9 transmembrane protein is a lysosomal arginine sensor that upon activation stimulates mTORC1 activity through the Rag GTPases. How Ragulator and SLC38A9 control the nucleotide loading state of the Rag GTPases remains incompletely understood. Here we find that Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state. Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP- to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Altogether, Ragulator and SLC38A9 act on the Rag GTPases to activate themTORC1 pathway in response to nutrient sufficiency.
The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping ...of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway's central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.
Regulation of mTORC1 by amino acids Bar-Peled, Liron; Sabatini, David M
Trends in cell biology,
07/2014, Letnik:
24, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Highlights • Cellular amino acid levels tightly control the activity of the master growth regulator mTORC1. • The emergence of molecular details on how the mTORC1 pathway senses amino acids is an ...important advance in the field. • The amino acid sensing pathway is composed of several multicomponent complexes that act in concert to convey changes in amino acid levels to mTORC1.
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