Making new contacts: the mTOR network in metabolism and signalling crosstalk

Shimobayashi, Mitsugu; Hall, Michael N.

doi:10.1038/nrm3757

Cited by 949 publications

(948 citation statements)

References 85 publications

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“…There was a trend for increased lipogenic metabolic genes and decreased glycolytic genes in CD4 + and CD8 + T cells that regulate their differentiation and function (Table S1) consistent with known rapamycin effects (Shimobayashi & Hall, 2014). …”

Section: Resultssupporting

confidence: 70%

“…Rapamycin is considered primarily an mTORC1 inhibitor (Laplante & Sabatini, 2012) but can also inhibit mTORC2. Recent studies distinguish mTORC1 versus mTORC2 effects on lifespan (Selman et al ., 2009) in addition to effects on cell proliferation (Dowling et al ., 2010), metabolism (Sengupta et al ., 2010; Lamming et al ., 2012), protein translation (Thoreen et al ., 2012), immunity (Chi, 2012), and other processes (Yu et al ., 2010; Shimobayashi & Hall, 2014). …”

Section: Introductionmentioning

confidence: 99%

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Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

et al. 2015

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SummaryThe mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age‐related debilities including increasing antigen‐specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long‐term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T‐ and B‐lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer‐ and infection‐prone mice supporting disease mitigation as a mechanism for mTOR suppression‐mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension.

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Section: Resultssupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

et al. 2015

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“…This signaling axis could shed light on the mechanism underlying some metabolic disorder diseases, since mTORC1 has been demonstrated to control biosynthesis of protein, nucleotides and lipids. 174 For example, glucose-6-phosphate isomerase (GPI) deficiency is the second most frequent cause of inherited glycolytic erythroenzymopathy in humans. 175 GPI catalyzes the second step of glycolysis, reversible interconversion of G-6P and fructose-6-phosphate.…”

Section: Hk-ii-mediated Regulation Of Mtorc1 and Autophagymentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

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“…mTORC1 integrates environmental signals such as nutrients, growth factors, oxygen, and stress to regulate protein translation, metabolism, and cell growth (Laplante and Sabatini 2012;Jewell et al 2013;Shimobayashi and Hall 2014). Although growth factors stimulate mTORC1 activity, amino acids are required for complete activation of mTORC1 (Hara et al 1998).…”

mentioning

confidence: 99%

GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2

et al. 2015

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Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression.

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Making new contacts: the mTOR network in metabolism and signalling crosstalk

Cited by 949 publications

References 85 publications

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2

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