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| Open AccessInhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing
The role of folate metabolism in leukemic stem cells remains understudied. Here, the authors show that inhibition of mitochondrial folate metabolism leads to differentiation of leukemic cells through depletion of purines and suppression of mTORC1.
- Martha M. Zarou
- , Kevin M. Rattigan
- & G. Vignir Helgason
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Article
| Open AccessA spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling
Kang et al. reveal structural and functional differences in mitochondria across the hepatic lobule. Mitochondrial distinct phosphoproteome influences their functions highlighting how nutrient availability helps to shape mitochondria zonation.
- Sun Woo Sophie Kang
- , Rory P. Cunningham
- & Natalie Porat-Shliom
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Article
| Open AccessVWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes
mTORC1 adapts cellular metabolism in response to nutrient signals. Here, the authors identify VWCE as a negative regulator of amino acid-dependent mTORC1 signaling and a potential as a therapeutic target in prostate cancer treatments.
- Tianyu Zhao
- , Yuanyuan Guan
- & Ying Liu
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Article
| Open AccessO-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations
The neurofilament cytoskeleton is critical for axon function and can be dysregulated in disease. Here, the authors show that intracellular glycosylation regulates a key neurofilament protein.
- Duc T. Huynh
- , Kalina N. Tsolova
- & Michael Boyce
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Article
| Open AccessAryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier
Dietary zinc and plant-derived aryl hydrocarbon receptor (AHR) agonists are involved in maintaining intestinal epithelium integrity. The authors show that combined supplementation with AHR ligands and zinc might be effective in preventing inflammatory gut disorders.
- Xiuchuan (Lucas) Hu
- , Wenfeng Xiao
- & Christer Hogstrand
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Article
| Open AccessA HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis
Cholesterol synthesis is highly oxygen consuming but how it is regulated by oxygen levels has not been clear. Here, Dickson et al. identify a HIF-independent, oxygen-sensing pathway for controlling cholesterol synthesis in human cells involving hypoxic-mediated degradation of SREBP2.
- Anna S. Dickson
- , Tekle Pauzaite
- & James A. Nathan
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Article
| Open AccessLysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization
Cystinosis is a lysosomal storage disease that affects the kidney. Here, the authors use preclinical models and advanced profiling techniques to discover the mechanism by which defective cystine mobilization from lysosomes disrupts kidney cell function, offering insights into potential therapies.
- Marine Berquez
- , Zhiyong Chen
- & Alessandro Luciani
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Article
| Open AccessRedefining the role of AMPK in autophagy and the energy stress response
According to the current understanding in the field, AMPK promotes autophagy by activating ULK1 during energy stress. Here, authors show that AMPK is indeed a negative regulator of ULK1 and it suppresses autophagy in energy depleted cells.
- Ji-Man Park
- , Da-Hye Lee
- & Do-Hyung Kim
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Article
| Open AccessMethionine restriction constrains lipoylation and activates mitochondria for nitrogenic synthesis of amino acids
Methionine restriction (MR) provides metabolic benefits in many organisms. Here, the authors report that MR is sensed by yeast mitochondria as a sign of SAM deprivation; in response, the mitochondria redirect carbon metabolism to fuel nitrogen anabolism in a lipoate-dependent mechanism.
- Wen Fang
- , Liu Jiang
- & Cunqi Ye
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Article
| Open AccessHedgehog-mediated gut-taste neuron axis controls sweet perception in Drosophila
Food regulates taste perception, but the underlying molecular mechanisms are not clear. Here, the authors reveal that sugar intake in Drosophila induces the gut to secrete Hedgehog into the circulation that suppresses sweet taste, sugar perception and preference.
- Yunpo Zhao
- , Mohammed A. Khallaf
- & Mattias Alenius
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Article
| Open AccessIntracellular galectin-3 is a lipopolysaccharide sensor that promotes glycolysis through mTORC1 activation
The carbohydrate binding protein galectin-3 has been linked to diabetes and cancer. Here, authors show that galectin-3 is a sensor of LPS, an important modulator of the mTORC1 signaling, and a critical regulator of glucose metabolism.
- Xing Chen
- , Chunyu Yu
- & Yongfeng Shang
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Article
| Open AccessDietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis
Although T cell commitment to specific lineages coincides with the rearrangement of T cell receptor loci, it remains unclear whether metabolism also influences this process. Here, authors show that de novo hexosamine biosynthesis promotes αβ T cell lineage commitment and γδ-TCR diversity and can be modulated by dietary supplementation.
- Guy Werlen
- , Mei-Ling Li
- & Estela Jacinto
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Article
| Open AccessAutophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA
The role of eiptranscriptomic modifications in autophagy is unclear. Here, the authors show that the m6A reader YTHDF3 functions as a nutrient responder to recognize upregulated m6A modification, promoting FOXO3 translation to subsequently initiate autophagy.
- WeiChao Hao
- , MeiJuan Dian
- & Dong Xiao
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Article
| Open AccessDirect control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly
mTORC1 blocks lysosomal nutrient generation. Here, the authors show that mTORC1 inactivation triggers V-ATPase assembly, which rapidly initiates lysosomal acidification and degradation of protein contents throughout the lysosomal population.
- Edoardo Ratto
- , S. Roy Chowdhury
- & Wilhelm Palm
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Article
| Open AccessRibosome impairment regulates intestinal stem cell identity via ZAKɑ activation
Intestinal stem cells are responsible for replenishing cells within the high-turnover intestinal epithelium. Here they show that ribosome dynamics affect intestinal stem cell identity through a mechanism that is triggered by changes in nutrient availability.
- Joana Silva
- , Ferhat Alkan
- & William James Faller
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Article
| Open AccessSpatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter
AMP activated protein kinase (AMPK) is a master regulator of cellular metabolism, but how AMPK activity is spatiotemporally regulated remains unclear. Here, Schmitt et al develop a sensitive biosensor for AMPK, which they use to uncover mechanisms for AMPK activity in the lysosome and nucleus.
- Danielle L. Schmitt
- , Stephanie D. Curtis
- & Jin Zhang
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Article
| Open AccessO-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine
Leucyl-tRNA synthetase 1 (LARS1) is a leucine sensor for mTORC1 signaling and regulates leucine utilization depending on glucose availability. Here, the author show that O-GlcNAcylation of LARS1 is crucial for its ability to regulate mTORC1 activity and leucine metabolism upon glucose starvation.
- Kibum Kim
- , Hee Chan Yoo
- & Jung Min Han
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Article
| Open AccessQuantitative phosphoproteomic analyses identify STK11IP as a lysosome-specific substrate of mTORC1 that regulates lysosomal acidification
mTORC1, central regulator of cell growth and autophagy suppressor, is activated on the lysosome surface, but its local role in lysosomal biology remains unclear. Here the authors show STK11IP is a substrate of mTORC1 that regulates lysosomal acidification through V-ATPase and represses autophagy.
- Zhenzhen Zi
- , Zhuzhen Zhang
- & Yonghao Yu
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Article
| Open AccessStarvation-induced proteasome assemblies in the nucleus link amino acid supply to apoptosis
Upon starvation, cells coordinate protein disposal to recycle amino acids, although the role of the proteasome has been unclear. Here, the authors show that in the mammalian nucleus, proteasomes form condensates that dissolve following nutrient replenishment.
- Maxime Uriarte
- , Nadine Sen Nkwe
- & El Bachir Affar
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Article
| Open AccessConstitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation
Heteroplasmic mtDNA mutations cause disease in humans. Here, Chung et al find the PI3K-Akt-mTORC1 pathway constitutively activated in cells with the heteroplasmic m.3243 A > G mutation, and inhibition of the pathway cell autonomously reduces mutant mtDNA load and rescues mitochondrial bioenergetics.
- Chih-Yao Chung
- , Kritarth Singh
- & Michael R. Duchen
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Article
| Open AccessTwo parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis
The metabolism of amino acids and the cellular energy sensor AMPK are both connected to mTORC1, but the pathway details have not been well defined. Here, the authors show that glutamine metabolism and mTORC1 have two regulatory connections with relevance to cancer therapeutics design.
- Clément Bodineau
- , Mercedes Tomé
- & Raúl V. Durán
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Article
| Open AccessGαq activation modulates autophagy by promoting mTORC1 signaling
Nutrient status in the cell regulates autophagy via mTORC1 activity. Here, the authors show that the ubiquitous G protein subunit Gαq contributes to nutrient sensing by promoting formation of an mTOR-p62-Raptor complex in replete conditions, modulating autophagy.
- Sofía Cabezudo
- , Maria Sanz-Flores
- & Catalina Ribas
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Article
| Open AccessGlucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development
Memory T cells are particularly reliant on fatty acid oxidation as a source of energy. Here the authors show this reliance is controlled by AMPK sensing of glucose deprivation that triggers SENP1-Sirt3 signalling, driving fatty acid oxidation and memory differentiation in T cells via deacetylation of YME1L1 to induce mitochondrial fusion.
- Jianli He
- , Xun Shangguan
- & Jinke Cheng
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Article
| Open AccessSelectivity of mRNA degradation by autophagy in yeast
Autophagic degradation of proteins and organelles is well studied, but the role of autophagy in RNA regulation is unclear. Here, the authors profile mRNAs targeted to the vacuole in yeast and observe autophagy-mediated mRNA degradation is not random but rather is a preferential process.
- Shiho Makino
- , Tomoko Kawamata
- & Yoshinori Ohsumi
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Article
| Open AccessmTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation
Glutathione peroxidase 4 (GPX4) inhibits ferroptosis, but protein synthesis is inefficient and costly. Here, the authors reveal that cystine uptake promotes GPX4 synthesis by activating mTORC1 and show that cancer cells are sensitized to ferroptosis by mTORC1 inhibition.
- Yilei Zhang
- , Robert V. Swanda
- & Boyi Gan
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Article
| Open AccessAutophagy sustains glutamate and aspartate synthesis in Saccharomyces cerevisiae during nitrogen starvation
Autophagy is known to promote cellular survival upon starvation, although how recycled components fit into cellular metabolism has not been well established. Here, the authors show in yeast that autophagy tunes cellular metabolism based on nitrogen availability via glutamate and aspartate synthesis.
- Kuanqing Liu
- , Benjamin M. Sutter
- & Benjamin P. Tu
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Article
| Open AccessYeast homologs of human MCUR1 regulate mitochondrial proline metabolism
Although some fungal mitochondria lack the calcium uniporter, many intriguingly encode homologs of the uniporter assembly factor MCUR1. Here, the authors show that in budding yeast, the MCUR1 homologs Put6 and Put7 regulate mitochondrial proline metabolism, a function also conserved in human MCUR1.
- Mohammad Zulkifli
- , John K. Neff
- & Vishal M. Gohil
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Article
| Open AccessPolyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction
Metabolic reprogramming during Dietary Restriction (DR) activates cytoprotective gene expression. Here the authors show that PUFAs generated during DR signal via the p38-MAPK pathway to enhance cytoprotective gene expression, contributing to increased longevity.
- Manish Chamoli
- , Anita Goyala
- & Arnab Mukhopadhyay
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Article
| Open AccessCD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis
The mechanistic details of fatty acid uptake into cells remains poorly understood. Here, the authors identify CD36 internalization via cavaeolae and demonstrate dynamic palmitoylationof CD36 is required for endocytic uptake of fatty acids.
- Jian-Wei Hao
- , Juan Wang
- & Tong-Jin Zhao
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Article
| Open AccessABHD11 maintains 2-oxoglutarate metabolism by preserving functional lipoylation of the 2-oxoglutarate dehydrogenase complex
2-oxoglutarate links mitochondrial metabolism to oxygen sensing, gene transcription and epigenetic modifications. Here, the authors describe a mutagenesis screen to find genes that control 2-oxoglutarate levels, and identify ABHD11 as a mitochondrial regulator of 2-oxoglutarate abundance.
- Peter S. J. Bailey
- , Brian M. Ortmann
- & James A. Nathan
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Article
| Open AccessLeucine regulates autophagy via acetylation of the mTORC1 component raptor
Leucine is a critical amino acid that inhibits autophagy. Here, the authors show that the leucine inhibits autophagy in most cell types, predominantly via its catabolite acetyl CoA, which drives acetylation of raptor, which activates mTORC1, a negative regulator of this catabolic process.
- Sung Min Son
- , So Jung Park
- & David C. Rubinsztein
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Article
| Open AccessRab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth
Charcot-Marie-Tooth (CMT) is an inherited peripheral neuropathy. Here, the authors show that Rab35 forms a complex with genes implicated in CMT, MTMR13 and MTMR2, which regulates myelin growth by controlling mTORC1 signaling through lipid turnover.
- Linda Sawade
- , Federica Grandi
- & Volker Haucke
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Article
| Open AccessRegulated repression governs the cell fate promoter controlling yeast meiosis
In budding yeast, the decision to enter meiosis is defined by nutrient and mating-type signals regulating expression of the master transcription factor for meiotic entry, IME1. Here, the authors characterize the steps involved in regulating the entering in meiosis via the co-repressor complex Tup1-Cyc8.
- Janis Tam
- & Folkert J. van Werven
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Article
| Open AccessSpatiotemporal contact between peroxisomes and lipid droplets regulates fasting-induced lipolysis via PEX5
Lipid droplets are organelles that regulate lipid metabolism but if organellar contacts play a role during lipolysis is unclear. Here, the authors show that peroxisomes and peroxisomal protein PEX5 play pivotal roles in the spatial and temporal regulation of fasting-induced lipolysis by translocating ATGL onto lipid droplets
- Jinuk Kong
- , Yul Ji
- & Jae Bum Kim
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Article
| Open AccessMiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1
Pancreatic ductal adenocarcinoma must adapt to a nutrient-poor microenvironment. Here, the authors show that miR-135 accumulates in response to glutamine deprivation and inhibits aerobic glycolysis by targeting phosphofructokinase-1, thereby redirecting glucose carbon to the TCA cycle and allowing pancreatic cancer cells survival.
- Ying Yang
- , Mari B. Ishak Gabra
- & Mei Kong
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Article
| Open AccessAmino acids stimulate the endosome-to-Golgi trafficking through Ragulator and small GTPase Arl5
Amino acid levels are known to regulate anabolic and catabolic pathways. Here, the authors report that amino acids also affect membrane trafficking by stimulating endosome-to-Golgi retrograde trafficking and regulating cell surface localization of certain Golgi proteins through Ragulator and Arl5.
- Meng Shi
- , Bing Chen
- & Lei Lu
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Article
| Open AccessSrc regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction
The growth-promoting activity of mTORC1 is regulated by amino acid availability via the Rag GTPases. Here, the authors demonstrate Src-dependent control of cell size and autophagy through disruption of the Rag GTPase–GATOR1 complex and mTORC1 activation at the lysosomal surface.
- Rituraj Pal
- , Michela Palmieri
- & Marco Sardiello
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Article
| Open AccessPhysiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing
High protein diets are known to improve metabolic parameters including adiposity and glucose homeostasis. Here the authors demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by peptide transporter 1 improve glucose homeostasis by inhibiting hepatic glucose production.
- Helen J. Dranse
- , T. M. Zaved Waise
- & Tony K. T. Lam
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Article
| Open AccessMAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB
Amino acids stimulate cell growth and depletion in a cell activates autophagy, yet how this is regulated is unclear. Here, the authors show that MAP4K3 (also known as germinal-center kinase-like kinase) acts as an amino acid-dependent regulator of autophagy, via phosphorylation of the transcription factor EB.
- Cynthia L. Hsu
- , Elian X. Lee
- & Albert R. La Spada
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Article
| Open Accessα-cell glucokinase suppresses glucose-regulated glucagon secretion
Glucagon secretion is promoted during hypoglycemia and inhibited by increased glucose levels. Here, Basco et al. show that glucokinase suppresses glucose-regulated glucagon secretion by modulating the intracellular ATP/ADP ratio and the closure of KATP channels in α-cells.
- Davide Basco
- , Quan Zhang
- & Bernard Thorens
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Article
| Open AccessStructural basis for the assembly of the Ragulator-Rag GTPase complex
mTORC1 activity is controlled through Rag GTPases, which are anchored to the lysosome through the Ragulator. Here, the authors give molecular insights into Ragulator-Rag GTPase assembly and present the crystal structures of the Ragulator alone and in complex with the RagA-C roadblock domains.
- Ryo Yonehara
- , Shigeyuki Nada
- & Masato Okada
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Article
| Open AccessFructose-1,6-bisphosphate couples glycolytic flux to activation of Ras
Yeast and cancer cells both favor sugar fermentation in aerobic conditions. Here the authors describe a conserved mechanism from yeast to mammals where the glycolysis intermediate fructose-1,6-bisphosphate binds Cdc25/Sos1 and couples increased glycolytic flux to increased Ras proto-oncoprotein activity.
- Ken Peeters
- , Frederik Van Leemputte
- & Johan M. Thevelein
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Article
| Open AccessEnergy stress-induced lncRNA FILNC1 represses c-Myc-mediated energy metabolism and inhibits renal tumor development
FoxO are commonly down-regulated transcription factors and tumor suppressors in renal cell cancer (RCC). Here, the authors show that upon energy stress FoxOs induce the expression of the long non-coding RNA FILNC1, which inhibits survival of RCC by downregulating c-Myc and c-Myc-dependent metabolic rewiring.
- Zhen-Dong Xiao
- , Leng Han
- & Boyi Gan
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Article
| Open AccessControl of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction
Leucyl-tRNA synthetase (LRS) is a leucine sensor of the mTORC1 pathway. Here, the authors identify inhibitors of the GTPase activating function of LRS, not affecting its catalytic activity, and demonstrate that the leucine sensor function of LRS can be a new target for mTORC1 inhibition.
- Jong Hyun Kim
- , Chulho Lee
- & Sunghoon Kim
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Article
| Open AccessEnoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients
Overnutrition has been linked to increased risk of cancer. Here, the authors show that exceeding nutrients suppress Enoyl-CoA hydratase-1 (ECHS1) activity by inducing its acetylation resulting in accumulation of fatty acids and branched-chain amino acids and oncogenic mTOR activation.
- Ya-Kun Zhang
- , Yuan-Yuan Qu
- & Wei Xu
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Article
| Open AccessGlutamine metabolism regulates autophagy-dependent mTORC1 reactivation during amino acid starvation
mTORC1 is a critical kinase that regulates cell growth and proliferation. Here the authors show that glutamine metabolism is sufficient to restore mTORC1 activity during prolonged amino acid starvation in an autophagy-dependent manner.
- Hayden Weng Siong Tan
- , Arthur Yi Loong Sim
- & Yun Chau Long
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Article
| Open AccessRaptor regulates functional maturation of murine beta cells
mTORC1 regulates beta cell survival, function and adaptation to physiologic and pathological stimuli. Here Niet al. demonstrate that that deficiency of Raptor, a component of mTORC1 complex, impairs insulin secretion and glucose tolerance in mice by affecting maturation of beta cells during the postnatal period.
- Qicheng Ni
- , Yanyun Gu
- & Qidi Wang
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Article
| Open AccessGlucose represses dendritic cell-induced T cell responses
Glucose is an important nutrient that feeds into glycolytic control of T cell function and differentiation. Here the authors show that T cells are superior to dendritic cells (DC) at glucose uptake, and by depriving DCs of this nutrient in their microenvironment T cells activate DC proinflammatory functions, which in turn enhance T cell effector functions in DC-T cell cocultures.
- Simon J. Lawless
- , Nidhi Kedia-Mehta
- & David K. Finlay
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Article
| Open AccessSirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins
The deacetylase Sirt1, known to regulate many cellular functions, can be activated by energy deprivation, however the mechanism is unclear. Here, the authors show that ATP inhibits Sirt1 by binding to the C-terminal domain, and energy deprivation derepresses Sirt1 activity by lowering the ATP level.
- Hyeog Kang
- , Shinichi Oka
- & Jay H. Chung