mTORC1 and mTORC2 selectively regulate CD8⁺ T cell differentiation.
Pollizzi Kristen N,Patel Chirag H,Sun Im-Hong,Oh Min-Hee,Waickman Adam T,Wen Jiayu,Delgoffe Greg M,Powell Jonathan D
The Journal of clinical investigation
Activation of mTOR-dependent pathways regulates the specification and differentiation of CD4+ T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) and mTORC2 have distinct roles in the generation of CD8+ T cell effector and memory populations. Evaluation of mice with a T cell-specific deletion of the gene encoding the negative regulator of mTORC1, tuberous sclerosis complex 2 (TSC2), resulted in the generation of highly glycolytic and potent effector CD8+ T cells; however, due to constitutive mTORC1 activation, these cells retained a terminally differentiated effector phenotype and were incapable of transitioning into a memory state. In contrast, CD8+ T cells deficient in mTORC1 activity due to loss of RAS homolog enriched in brain (RHEB) failed to differentiate into effector cells but retained memory characteristics, such as surface marker expression, a lower metabolic rate, and increased longevity. However, these RHEB-deficient memory-like T cells failed to generate recall responses as the result of metabolic defects. While mTORC1 influenced CD8+ T cell effector responses, mTORC2 activity regulated CD8+ T cell memory. mTORC2 inhibition resulted in metabolic reprogramming, which enhanced the generation of CD8+ memory cells. Overall, these results define specific roles for mTORC1 and mTORC2 that link metabolism and CD8+ T cell effector and memory generation and suggest that these functions have the potential to be targeted for enhancing vaccine efficacy and antitumor immunity.
Caveat mTOR: aberrant signaling disrupts corticogenesis.
Osborne Lucy R
The Journal of clinical investigation
The mammalian target of rapamycin (mTOR) signaling pathway is activated in several disorders associated with benign tumors and malformations of the cerebral cortex. In this issue of the JCI, Orlova et al. have now definitively added another disorder to this group by demonstrating that activation of mTOR signaling is associated with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE), which is characterized by severe intractable epilepsy and megalencephaly. PMSE is caused by lack of the pseudokinase STE20-related kinase adaptor alpha (STRADalpha), and Orlova et al. show that reduction of STRADalpha levels during corticogenesis in the mouse results in a cellular phenotype and neuronal migration defects similar to those observed in patients with PMSE, clearly demonstrating a pivotal role for STRADalpha in cell polarity and growth. This study helps pave the way for possible therapeutic intervention with rapamycin to control the epilepsy and learning disabilities associated with this disorder.
Critical role for hypothalamic mTOR activity in energy balance.
Mori Hiroyuki,Inoki Ken,Münzberg Heike,Opland Darren,Faouzi Miro,Villanueva Eneida C,Ikenoue Tsuneo,Kwiatkowski David,MacDougald Ormond A,Myers Martin G,Guan Kun-Liang
The mammalian target of rapamycin (mTOR) promotes anabolic cellular processes in response to growth factors and metabolic cues. The TSC1 and TSC2 tumor suppressors are major upstream inhibitory regulators of mTOR signaling. Mice with Rip2/Cre-mediated deletion of Tsc1 (Rip-Tsc1cKO mice) developed hyperphagia and obesity, suggesting that hypothalamic disruption (for which Rip2/Cre is well known) of Tsc1 may dysregulate feeding circuits via mTOR activation. Indeed, Rip-Tsc1cKO mice displayed increased mTOR signaling and enlarged neuron cell size in a number of hypothalamic populations, including Pomc neurons. Furthermore, Tsc1 deletion with Pomc/Cre (Pomc-Tsc1cKO mice) resulted in dysregulation of Pomc neurons and hyperphagic obesity. Treatment with the mTOR inhibitor, rapamycin, ameliorated the hyperphagia, obesity, and the altered Pomc neuronal morphology in developing or adult Pomc-Tsc1cKO mice, and cessation of treatment reinstated these phenotypes. Thus, ongoing mTOR activation in Pomc neurons blocks the catabolic function of these neurons to promote nutrient intake and increased adiposity.
DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212.
Kim Ju Young,Duan Xin,Liu Cindy Y,Jang Mi-Hyeon,Guo Junjie U,Pow-anpongkul Nattapol,Kang Eunchai,Song Hongjun,Ming Guo-li
Disrupted-in-schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here, we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to overactivated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies the AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.
Amino acid signalling upstream of mTOR.
Jewell Jenna L,Russell Ryan C,Guan Kun-Liang
Nature reviews. Molecular cell biology
Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that is part of mTOR complex 1 (mTORC1), a master regulator that couples amino acid availability to cell growth and autophagy. Multiple cues modulate mTORC1 activity, such as growth factors, stress, energy status and amino acids. Although amino acids are key environmental stimuli, exactly how they are sensed and how they activate mTORC1 is not fully understood. Recently, a model has emerged whereby mTORC1 activation occurs at the lysosome and is mediated through an amino acid sensing cascade involving RAG GTPases, Ragulator and vacuolar H(+)-ATPase (v-ATPase).
The neurology of mTOR.
Lipton Jonathan O,Sahin Mustafa
The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.
The mTOR signalling cascade: paving new roads to cure neurological disease.
Crino Peter B
Nature reviews. Neurology
Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.
mTOR in Brain Physiology and Pathologies.
Bockaert Joël,Marin Philippe
TOR (target of rapamycin) and its mammalian ortholog mTOR have been discovered in an effort to understand the mechanisms of action of the immunosuppressant drug rapamycin extracted from a bacterium of the Easter Island (Rapa Nui) soil. mTOR is a serine/threonine kinase found in two functionally distinct complexes, mTORC1 and mTORC2, which are differentially regulated by a great number of nutrients such as glucose and amino acids, energy (oxygen and ATP/AMP content), growth factors, hormones, and neurotransmitters. mTOR controls many basic cellular functions such as protein synthesis, energy metabolism, cell size, lipid metabolism, autophagy, mitochondria, and lysosome biogenesis. In addition, mTOR-controlled signaling pathways regulate many integrated physiological functions of the nervous system including neuronal development, synaptic plasticity, memory storage, and cognition. Thus it is not surprising that deregulation of mTOR signaling is associated with many neurological and psychiatric disorders. Preclinical and preliminary clinical studies indicate that inhibition of mTORC1 can be beneficial for some pathological conditions such as epilepsy, cognitive impairment, and brain tumors, whereas stimulation of mTORC1 (direct or indirect) can be beneficial for other pathologies such as depression or axonal growth and regeneration.
mTOR Signaling in Growth, Metabolism, and Disease.
Saxton Robert A,Sabatini David M
The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.