TOR signalling

  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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