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| Open AccessHepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver
The liver is segregated into spatially organized areas that serve distinct functions, though how these zones are patterned remains unclear. Here they show that mTORC1 controls spatial segregation of liver metabolic functions via modulation of Wnt signaling, and find that impaired zonation is also observed in pigs given total parenteral nutrition.
- Ana Belén Plata-Gómez
- , Lucía de Prado-Rivas
- & Alejo Efeyan
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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 AccessWhole-genome screens reveal regulators of differentiation state and context-dependent migration in human neutrophils
Neutrophils provide a critical early defense as part of our innate immune system. Here, authors performed a genome-wide assessment of the molecular factors critical to proliferation, differentiation, and cell migration in a neutrophil-like cell.
- Nathan M. Belliveau
- , Matthew J. Footer
- & Julie A. Theriot
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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 AccessMolecular basis of mEAK7-mediated human V-ATPase regulation
Structural basis of V-ATPase regulation by endogenous proteins is unclear. Here, the authors find mEAK7 as an endogenous V-ATPase modulator and determine its structure with V-ATPase, suggesting the potential role of mEAK7 in V-ATPase regulation.
- Rong Wang
- , Yu Qin
- & Xiaochun Li
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| 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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| Open AccessSARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition
The pandemic of COVID-19, caused by SARS-CoV-2 infection, warrants immediate investigation for therapy options. Here the authors show, using epithelial and air-liquid interface cultures, that SARS-CoV-2 hijacks host cell metabolism to facilitate viral replication, and that inhibition of mTORC1, a master metabolic regulator, suppresses viral replication.
- Peter J. Mullen
- , Gustavo Garcia Jr
- & Heather R. Christofk
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| Open AccessMutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.
- Takeshi Fujino
- , Susumu Goyama
- & Toshio Kitamura
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Article
| Open AccessmTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability
mTORC1 is a key mediator of drug resistance and also regulates autophagy. In this study, the authors demonstrate that cancer cells with acquired drug resistance exibit metabolic vulnerabilities mediated by high levels of mTORC1 and the consequent inhibition of autophagy.
- Niklas Gremke
- , Pierfrancesco Polo
- & Thorsten Stiewe
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| Open AccessMacropinocytosis drives T cell growth by sustaining the activation of mTORC1
Macropinocytosis has been implicated in the expansion of transformed cells when nutrient-depleted. Here the authors show that macropinocytosis also contributes to the expansion of primary T cells even under nutrient-replete conditions, potentially by providing access of extracellular amino acids to an endolysosomal compartment to sustain mTORC1 activation.
- John C. Charpentier
- , Di Chen
- & Philip D. King
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Article
| Open AccessPHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase
mTORC1 is an important regulator of muscle mass. Here, the authors show that the PHD1 controls muscle mass in a hydroxylation-independent manner. PHD1 prevents the degradation of leucine sensor LRS during oxygen and amino acid depletion to ensure effective mTORC1 activation in response to leucine.
- Gommaar D’Hulst
- , Inés Soro-Arnaiz
- & Katrien De Bock
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Article
| Open AccessFoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism
Insulin signaling represses Forkhead transcription factor FoxO activity, which contributes to organismal metabolism. Here, the authors use proteomics to identify positively regulated insulin signaling targets FoxK1/K2 and demonstrate their role in lipid metabolism and mitochondrial regulation.
- Masaji Sakaguchi
- , Weikang Cai
- & C. Ronald Kahn
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Article
| Open AccessShp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells
The phosphatase Shp-2 was implicated in NK cell education due to its reported association with inhibitory receptors, but its function in this context is unclear. Here the authors show that Shp-2 is not required for NK cell function, but is necessary for IL-15-induced metabolic burst and expansion.
- Charlène Niogret
- , S. M. Shahjahan Miah
- & Greta Guarda
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| Open AccessThe mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
The PI3K/Akt/mTOR pathway has been previously implicated in fibrosis and a pan-PI3K/mTOR inhibitor is currently under clinical evaluation for the treatment of IPF. Here the authors show that the mTORC1/4E-BP1 axis is critical for TGF-β1-induced fibrogenesis in in vitro and ex vivo models and that canonical PI3K/Akt signalling is dispensable.
- Hannah V. Woodcock
- , Jessica D. Eley
- & Rachel C. Chambers
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Article
| Open AccessInhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours
LncRNA H19 has been shown to be aberrantly expressed in different cancers. Here, the authors show that H19 lncRNA is downregulated in pituitary adenomas and H19 is able to impede pituitary tumorigenesis via disruption of 4E-BPB1 and Raptor interaction to inhibit the phosphorylation of 4E-BP1.
- Ze Rui Wu
- , Lichong Yan
- & Zhe Bao Wu
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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 AccessGlucose promotes cell growth by suppressing branched-chain amino acid degradation
Hypertrophic cardiomyocytes switch their metabolism from fatty acid oxidation to glucose use, but the functional role of this change is unclear. Here the authors show that high intracellular glucose inhibits the degradation of branched-chain amino acids, which is required for the activation of pro-growth mTOR signaling.
- Dan Shao
- , Outi Villet
- & Rong Tian
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| Open AccessDual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality
The Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways are essential for cancer cell survival. Here, the authors describes a molecule a131 with dual-inhibitory properties, which targets PI5P4K and mitosis, and it is involved in Ras/Raf/MEK/ERK and PI3K/Akt/mTOR crosstalk, thereby causing reversible growth arrest in normal cells and cell death of tumor cells.
- Mayumi Kitagawa
- , Pei-Ju Liao
- & Sang Hyun Lee
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Article
| Open AccessCryo-EM structure of Saccharomyces cerevisiae target of rapamycin complex 2
Target of rapamycin (TOR) kinase operates within two distinct multiprotein complexes named TORC1 and TORC2. Here the authors report a cryo-EM structure of TORC2, establish its subunit organization, providing a rationale for TORC2’s rapamycin insensitivity and the mutually exclusive inclusion of Avo3/Rictor or Raptor within their respective TOR complex.
- Manikandan Karuppasamy
- , Beata Kusmider
- & Christiane Schaffitzel
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Article
| Open AccessStructural basis for Ragulator functioning as a scaffold in membrane-anchoring of Rag GTPases and mTORC1
Activated Rag GTPases recruit mTORC1 to lysosomes. Here the authors present the crystal structure of the Ragulator complex and identify the binding sites for the Roadblock domains of Rag GTPases, which gives insights how Rag GTPases are tethered to the lysosomal membrane.
- Tianlong Zhang
- , Rong Wang
- & Jianping Ding
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Article
| Open AccessRETRACTED ARTICLE: Sulfur availability regulates plant growth via glucose-TOR signaling
Plants lack the amino acid sensors that regulate TOR in metazoans. Here Dong et al. show that Arabidopsis GCN2 senses carbon and nitrogen availability for cysteine synthesis while sulfur limitation activates TOR via glucose metabolism, providing a mechanism whereby plants control growth according to nutrient availability.
- Yihan Dong
- , Marleen Silbermann
- & Markus Wirtz
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Article
| Open AccessMembrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression
LKB1 regulates various cellular processes such as cell proliferation, energy homeostasis and cell polarity and is frequently downregulated in various tumours. Here the authors show that LKB1 activation requires direct binding to phospholipids and show this has an implication for carcinogenesis.
- Giada Dogliotti
- , Lars Kullmann
- & Michael P. Krahn
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| Open AccessEGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration
In response to gut epithelial damage,Drosophilastem cells proliferate to produce large polyploid enterocytes (EC), which comprise the bulk of the epithelium. Here, the authors show that stress-dependent EGFR/MAP kinase signalling drives both endoreplication and cell growth in newborn ECs.
- Jinyi Xiang
- , Jennifer Bandura
- & Bruce A. Edgar
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Article
| Open AccessmTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis
mTORC1 and mTORC2 are alternatively required for differentiation of T cells into Th1/Th17 or Th2 cells. Here the authors show mTORC2 signalling is also needed for IL-4-induced M2 activation with functional evidence provided by aN. brasiliensisinfection model and cold challenge to model adaptive thermogenesis.
- R. W. Hallowell
- , S. L. Collins
- & M. R. Horton
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| Open AccessmTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation
Inhibitors of the mTORC1 pathway are considered anti-cancer drugs. Here, the authors show that on nutrient restriction, glutaminolysis-induced activation of mTORC1 induces apoptosis via inhibiting autophagy, highlighting that under such conditions inhibition of mTORC1 results in survival of cancer cells.
- Victor H. Villar
- , Tra Ly Nguyen
- & Raúl V. Durán
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Article
| Open AccessThe oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway
Oncogenic mutations of isocitrate dehydrogenases 1 and 2 result in the production of the oncometabolite R-2-hydroxyglutarate. Here the authors show that the oncometabolite promotes mTOR activation in a PTEN/PI3K-independent manner by regulating DEPTOR stability via inhibition of KDM4A activity.
- Mélissa Carbonneau
- , Laurence M. Gagné
- & Frédérick A. Mallette
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| Open AccessProteome-wide association studies identify biochemical modules associated with a wing-size phenotype in Drosophila melanogaster
How genetic diversity generates complex phenotypes along a continuum remains a fundamental question of biology. Here—applying the emerging SWATH proteomics technology—the authors describe a proteome wide association study (PWAS) of Drosophila wing size and identify functional protein clusters associated with this trait.
- Hirokazu Okada
- , H. Alexander Ebhardt
- & Ernst Hafen
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| Open AccessRegulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes
The molecular mechanisms regulating myelination are only partially understood. Here authors show that Tsc1ablation in oligodendrocyte lineage activates ER stress and apoptotic programs in mice, and that enhancing PERK-eIF2α signalling partially rescues the myelination defects in Tsc1 mutants.
- Minqing Jiang
- , Lei Liu
- & Q. Richard Lu
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| Open Access14-3-3 proteins regulate Tctp–Rheb interaction for organ growth in Drosophila
14-3-3 proteins regulate several signalling pathways but often act redundantly; however, the molecular mechanisms behind such redundancy are unclear. Here, the authors show that 14-3-3 proteins regulate two interacting components of Tor signalling in Drosophila, Tctp and Rheb, disrupting organ development.
- Thao Phuong Le
- , Linh Thuong Vuong
- & Kwang-Wook Choi
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| Open AccessmTORC1 and CK2 coordinate ternary and eIF4F complex assembly
Ternary complex (TC) and eIF4F complex assembly are rate-limiting steps in translation initiation that are regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway. Here the authors show that the protein kinases mTORC1 and CK2 coordinate TC and eIF4F complex assembly through eIF2β to stimulate cell proliferation.
- Valentina Gandin
- , Laia Masvidal
- & Ivan Topisirovic
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| Open AccessMondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals
Removal of the C. elegans germline substantially increases organismal lifespan. Here, Nakamura et al. show that the transcription factors MML-1 and MXL-2 coordinate this process in that they reduce TOR signalling and increase autophagy by regulating activity of HLH-30.
- Shuhei Nakamura
- , Özlem Karalay
- & Adam Antebi
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| Open AccessSUMOylation of AMPKα1 by PIAS4 specifically regulates mTORC1 signalling
AMPK senses cellular energy and switches off pathways involved in protein and fatty acid synthesis, but the selectivity of AMPK for different pathways is unclear. Here, the authors show that PIAS4-dependent SUMOylation and inactivation of AMPK preferentially restores activity of the mTORC1 pathway.
- Yan Yan
- , Saara Ollila
- & Tomi P. Mäkelä
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| Open AccessLAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation
Essential amino acids such as leucine activate mTORC1 signalling after entering the lysosome, but the molecular basis for lysosomal amino-acid uptake is unclear. Here Milkereit et al. show that LAPTM4b, a lysosomal membrane protein, recruits a leucine transporter to the lysosome and promotes amino-acid influx and mTORC1 signalling.
- Ruth Milkereit
- , Avinash Persaud
- & Daniela Rotin
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| Open AccessLAMTOR2 regulates dendritic cell homeostasis through FLT3-dependent mTOR signalling
LAMTOR2 is involved in mTOR and ERK signalling and plays a role in immunity, but its function in dendritic cells (DCs) is not clear. Here the authors show that deletion of LAMTOR2 in DCs results in increased mTOR signalling, accumulation of Flt3 on the cell surface and excessive DC proliferation in ageing mice.
- Julia M. Scheffler
- , Florian Sparber
- & Lukas A. Huber
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The TORC1 effector kinase Npr1 fine tunes the inherent activity of the Mep2 ammonium transport protein
The TORC1 complex regulates cell growth and metabolism in response to nutrient availability. Boeckstaens et al.demonstrate that following amino-acid starvation, the TORC1 effector Npr1 stimulates ammonium uptake through the Mep2 transporter by phosphorylating and inactivating an inhibitory domain.
- Mélanie Boeckstaens
- , Elisa Llinares
- & Anna Maria Marini
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| Open AccessA shift of the TOR adaptor from Rictor towards Raptor by semaphorin in C. elegans
What controls the binding partner selection of the target of rapamycin protein, TOR, is unknown. Using theCaenorhabditis elegans tail as a model, Nukazuka et al. determine that signals of semaphorin through plexin control the binding partner selection of TOR and are required for the correct organization of rays in the tail.
- Akira Nukazuka
- , Shusaku Tamaki
- & Shin Takagi