Genes

Review

32 pages, 1936 KiB

Open AccessReview

MTOR Signaling and Metabolism in Early T Cell Development

by Guy Werlen, Ritika Jain and Estela Jacinto

Genes 2021, 12(5), 728; https://doi.org/10.3390/genes12050728 - 13 May 2021

Cited by 20 | Viewed by 6349

The mechanistic target of rapamycin (mTOR) controls cell fate and responses via its functions in regulating metabolism. Its role in controlling immunity was unraveled by early studies on the immunosuppressive properties of rapamycin. Recent studies have provided insights on how metabolic reprogramming and [...] Read more.

The mechanistic target of rapamycin (mTOR) controls cell fate and responses via its functions in regulating metabolism. Its role in controlling immunity was unraveled by early studies on the immunosuppressive properties of rapamycin. Recent studies have provided insights on how metabolic reprogramming and mTOR signaling impact peripheral T cell activation and fate. The contribution of mTOR and metabolism during early T-cell development in the thymus is also emerging and is the subject of this review. Two major T lineages with distinct immune functions and peripheral homing organs diverge during early thymic development; the αβ- and γδ-T cells, which are defined by their respective TCR subunits. Thymic T-regulatory cells, which have immunosuppressive functions, also develop in the thymus from positively selected αβ-T cells. Here, we review recent findings on how the two mTOR protein complexes, mTORC1 and mTORC2, and the signaling molecules involved in the mTOR pathway are involved in thymocyte differentiation. We discuss emerging views on how metabolic remodeling impacts early T cell development and how this can be mediated via mTOR signaling. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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14 pages, 1214 KiB

Open AccessReview

Conserved and Divergent Mechanisms That Control TORC1 in Yeasts and Mammals

by Yuichi Morozumi and Kazuhiro Shiozaki

Genes 2021, 12(1), 88; https://doi.org/10.3390/genes12010088 - 12 Jan 2021

Cited by 29 | Viewed by 4852

Abstract

Target of rapamycin complex 1 (TORC1), a serine/threonine-protein kinase complex highly conserved among eukaryotes, coordinates cellular growth and metabolism with environmental cues, including nutrients and growth factors. Aberrant TORC1 signaling is associated with cancers and various human diseases, and TORC1 also plays a [...] Read more.

Target of rapamycin complex 1 (TORC1), a serine/threonine-protein kinase complex highly conserved among eukaryotes, coordinates cellular growth and metabolism with environmental cues, including nutrients and growth factors. Aberrant TORC1 signaling is associated with cancers and various human diseases, and TORC1 also plays a key role in ageing and lifespan, urging current active research on the mechanisms of TORC1 regulation in a variety of model organisms. Identification and characterization of the RAG small GTPases as well as their regulators, many of which are highly conserved from yeast to humans, led to a series of breakthroughs in understanding the molecular bases of TORC1 regulation. Recruitment of mammalian TORC1 (mTORC1) by RAGs to lysosomal membranes is a key step for mTORC1 activation. Interestingly, the RAG GTPases in fission yeast are primarily responsible for attenuation of TORC1 activity on vacuoles, the yeast equivalent of lysosomes. In this review, we summarize our current knowledge about the functions of TORC1 regulators on yeast vacuoles, and illustrate the conserved and divergent mechanisms of TORC1 regulation between yeasts and mammals. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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15 pages, 893 KiB

Open AccessReview

The Plant Target of Rapamycin: A Conduc TOR of Nutrition and Metabolism in Photosynthetic Organisms

by Camille Ingargiola, Gustavo Turqueto Duarte, Christophe Robaglia, Anne-Sophie Leprince and Christian Meyer

Genes 2020, 11(11), 1285; https://doi.org/10.3390/genes11111285 - 29 Oct 2020

Cited by 27 | Viewed by 5698

Abstract

Living organisms possess many mechanisms to sense nutrients and favorable conditions, which allow them to grow and develop. Photosynthetic organisms are very diverse, from green unicellular algae to multicellular flowering plants, but most of them are sessile and thus unable to escape from [...] Read more.

Living organisms possess many mechanisms to sense nutrients and favorable conditions, which allow them to grow and develop. Photosynthetic organisms are very diverse, from green unicellular algae to multicellular flowering plants, but most of them are sessile and thus unable to escape from the biotic and abiotic stresses they experience. The Target of Rapamycin (TOR) signaling pathway is conserved in all eukaryotes and acts as a central regulatory hub between growth and extrinsic factors, such as nutrients or stress. However, relatively little is known about the regulations and roles of this pathway in plants and algae. Although some features of the TOR pathway seem to have been highly conserved throughout evolution, others clearly differ in plants, perhaps reflecting adaptations to different lifestyles and the rewiring of this primordial signaling module to adapt to specific requirements. Indeed, TOR is involved in plant responses to a vast array of signals including nutrients, hormones, light, stresses or pathogens. In this review, we will summarize recent studies that address the regulations of TOR by nutrients in photosynthetic organisms, and the roles of TOR in controlling important metabolic pathways, highlighting similarities and differences with the other eukaryotes. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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19 pages, 2927 KiB

Open AccessReview

Regulation of mTORC2 Signaling

by Wenxiang Fu and Michael N. Hall

Genes 2020, 11(9), 1045; https://doi.org/10.3390/genes11091045 - 4 Sep 2020

Cited by 137 | Viewed by 14005

Abstract

Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase and a master regulator of cell growth and metabolism, forms two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. While mTORC1 signaling is well characterized, mTORC2 is relatively poorly understood. mTORC2 [...] Read more.

Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase and a master regulator of cell growth and metabolism, forms two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. While mTORC1 signaling is well characterized, mTORC2 is relatively poorly understood. mTORC2 appears to exist in functionally distinct pools, but few mTORC2 effectors/substrates have been identified. Here, we review recent advances in our understanding of mTORC2 signaling, with particular emphasis on factors that control mTORC2 activity. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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20 pages, 1903 KiB

Open AccessReview

The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

by Ivana Bjedov and Charalampos Rallis

Genes 2020, 11(9), 1043; https://doi.org/10.3390/genes11091043 - 3 Sep 2020

Cited by 72 | Viewed by 11469

Abstract

Ageing is a complex trait controlled by genes and the environment. The highly conserved mechanistic target of rapamycin signalling pathway (mTOR) is a major regulator of lifespan in all eukaryotes and is thought to be mediating some of the effects of dietary restriction. [...] Read more.

Ageing is a complex trait controlled by genes and the environment. The highly conserved mechanistic target of rapamycin signalling pathway (mTOR) is a major regulator of lifespan in all eukaryotes and is thought to be mediating some of the effects of dietary restriction. mTOR is a rheostat of energy sensing diverse inputs such as amino acids, oxygen, hormones, and stress and regulates lifespan by tuning cellular functions such as gene expression, ribosome biogenesis, proteostasis, and mitochondrial metabolism. Deregulation of the mTOR signalling pathway is implicated in multiple age-related diseases such as cancer, neurodegeneration, and auto-immunity. In this review, we briefly summarise some of the workings of mTOR in lifespan and ageing through the processes of transcription, translation, autophagy, and metabolism. A good understanding of the pathway’s outputs and connectivity is paramount towards our ability for genetic and pharmacological interventions for healthy ageing and amelioration of age-related disease. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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28 pages, 1791 KiB

Open AccessReview

Regulation of mTORC1 by Upstream Stimuli

by Chase H. Melick and Jenna L. Jewell

Genes 2020, 11(9), 989; https://doi.org/10.3390/genes11090989 - 25 Aug 2020

Cited by 69 | Viewed by 12598

Abstract

The mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr protein kinase that senses multiple upstream stimuli to control cell growth, metabolism, and autophagy. mTOR is the catalytic subunit of mTOR complex 1 (mTORC1). A significant amount of research has uncovered the [...] Read more.

The mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr protein kinase that senses multiple upstream stimuli to control cell growth, metabolism, and autophagy. mTOR is the catalytic subunit of mTOR complex 1 (mTORC1). A significant amount of research has uncovered the signaling pathways regulated by mTORC1, and the involvement of these signaling cascades in human diseases like cancer, diabetes, and ageing. Here, we review advances in mTORC1 regulation by upstream stimuli. We specifically focus on how growth factors, amino acids, G-protein coupled receptors (GPCRs), phosphorylation, and small GTPases regulate mTORC1 activity and signaling. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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11 pages, 809 KiB

Open AccessReview

Novel Links between TORC1 and Traditional Non-Coding RNA, tRNA

by Yoko Otsubo, Yoshiaki Kamada and Akira Yamashita

Genes 2020, 11(9), 956; https://doi.org/10.3390/genes11090956 - 19 Aug 2020

Cited by 12 | Viewed by 3517

Abstract

Target of rapamycin (TOR) is a serine/threonine kinase that modulates cell growth and metabolism in response to environmental changes. Transfer RNA (tRNA) is an abundant and ubiquitous small non-coding RNA that is essential in the translation of mRNAs. Beyond its canonical role, it [...] Read more.

Target of rapamycin (TOR) is a serine/threonine kinase that modulates cell growth and metabolism in response to environmental changes. Transfer RNA (tRNA) is an abundant and ubiquitous small non-coding RNA that is essential in the translation of mRNAs. Beyond its canonical role, it has been revealed that tRNAs have more diverse functions. TOR complex 1 (TORC1), which is one of the two TOR complexes, regulates tRNA synthesis by controlling RNA polymerase III. In addition to tRNA synthesis regulation, recent studies have revealed hidden connections between TORC1 and tRNA, which are both essential players in eukaryotic cellular activities. Here, we review the accumulating findings on the regulatory links between TORC1 and tRNA—particularly those links in the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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9 pages, 989 KiB

Open AccessReview

Pathological Consequences of Hepatic mTORC1 Dysregulation

by Chun-Seok Cho, Allison Ho Kowalsky and Jun Hee Lee

Genes 2020, 11(8), 896; https://doi.org/10.3390/genes11080896 - 5 Aug 2020

Cited by 9 | Viewed by 3571

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of metabolism that integrates environmental inputs, including nutrients, growth factors, and stress signals. mTORC1 activation upregulates anabolism of diverse macromolecules, such as proteins, lipids, and nucleic acids, while downregulating autolysosomal catabolism. [...] Read more.

The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of metabolism that integrates environmental inputs, including nutrients, growth factors, and stress signals. mTORC1 activation upregulates anabolism of diverse macromolecules, such as proteins, lipids, and nucleic acids, while downregulating autolysosomal catabolism. mTORC1 dysregulation is often found in various diseases, including cancer, cardiovascular and neurodegenerative diseases, as well as metabolic syndromes involving obesity and type II diabetes. As an essential metabolic organ, the liver requires proper regulation of mTORC1 for maintaining homeostasis and preventing pathologies. For instance, aberrant hyper- or hypoactivation of mTORC1 disrupts hepatocellular homeostasis and damages the structural and functional integrity of the tissue, leading to prominent liver injury and the development of hepatocellular carcinogenesis. Proper regulation of mTORC1 during liver diseases may be beneficial for restoring liver function and ameliorating the detrimental consequences of liver failure. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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24 pages, 4540 KiB

Open AccessReview

Structural Insights into TOR Signaling

by Lucas Tafur, Jennifer Kefauver and Robbie Loewith

Genes 2020, 11(8), 885; https://doi.org/10.3390/genes11080885 - 4 Aug 2020

Cited by 30 | Viewed by 7509

Abstract

The Target of Rapamycin (TOR) is a highly conserved serine/threonine protein kinase that performs essential roles in the control of cellular growth and metabolism. TOR acts in two distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in humans), which maintain different aspects [...] Read more.

The Target of Rapamycin (TOR) is a highly conserved serine/threonine protein kinase that performs essential roles in the control of cellular growth and metabolism. TOR acts in two distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in humans), which maintain different aspects of cellular homeostasis and orchestrate the cellular responses to diverse environmental challenges. Interest in understanding TOR signaling is further motivated by observations that link aberrant TOR signaling to a variety of diseases, ranging from epilepsy to cancer. In the last few years, driven in large part by recent advances in cryo-electron microscopy, there has been an explosion of available structures of (m)TORC1 and its regulators, as well as several (m)TORC2 structures, derived from both yeast and mammals. In this review, we highlight and summarize the main findings from these reports and discuss both the fascinating and unexpected molecular biology revealed and how this knowledge will potentially contribute to new therapeutic strategies to manipulate signaling through these clinically relevant pathways. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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19 pages, 921 KiB

Open AccessReview

Experimental Approaches in Delineating mTOR Signaling

by Jiayi Qian, Siyuan Su and Pengda Liu

Genes 2020, 11(7), 738; https://doi.org/10.3390/genes11070738 - 2 Jul 2020

Cited by 10 | Viewed by 5351

Abstract

The mTOR signaling controls essential biological functions including proliferation, growth, metabolism, autophagy, ageing, and others. Hyperactivation of mTOR signaling leads to a plethora of human disorders; thus, mTOR is an attractive drug target. The discovery of mTOR signaling started from isolation of rapamycin [...] Read more.

The mTOR signaling controls essential biological functions including proliferation, growth, metabolism, autophagy, ageing, and others. Hyperactivation of mTOR signaling leads to a plethora of human disorders; thus, mTOR is an attractive drug target. The discovery of mTOR signaling started from isolation of rapamycin in 1975 and cloning of TOR genes in 1993. In the past 27 years, numerous research groups have contributed significantly to advancing our understanding of mTOR signaling and mTOR biology. Notably, a variety of experimental approaches have been employed in these studies to identify key mTOR pathway members that shape up the mTOR signaling we know today. Technique development drives mTOR research, while canonical biochemical and yeast genetics lay the foundation for mTOR studies. Here in this review, we summarize major experimental approaches used in the past in delineating mTOR signaling, including biochemical immunoprecipitation approaches, genetic approaches, immunofluorescence microscopic approaches, hypothesis-driven studies, protein sequence or motif search driven approaches, and bioinformatic approaches. We hope that revisiting these distinct types of experimental approaches will provide a blueprint for major techniques driving mTOR research. More importantly, we hope that thinking and reasonings behind these experimental designs will inspire future mTOR research as well as studies of other protein kinases beyond mTOR. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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15 pages, 1456 KiB

Open AccessReview

Reciprocal Regulation between Primary Cilia and mTORC1

by Yandong Lai and Yu Jiang

Genes 2020, 11(6), 711; https://doi.org/10.3390/genes11060711 - 26 Jun 2020

Cited by 20 | Viewed by 7077

Abstract

In quiescent cells, primary cilia function as a mechanosensor that converts mechanic signals into chemical activities. This unique organelle plays a critical role in restricting mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is essential for quiescent cells to maintain their quiescence. [...] Read more.

In quiescent cells, primary cilia function as a mechanosensor that converts mechanic signals into chemical activities. This unique organelle plays a critical role in restricting mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is essential for quiescent cells to maintain their quiescence. Multiple mechanisms have been identified that mediate the inhibitory effect of primary cilia on mTORC1 signaling. These mechanisms depend on several tumor suppressor proteins localized within the ciliary compartment, including liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK), polycystin-1, and polycystin-2. Conversely, changes in mTORC1 activity are able to affect ciliogenesis and stability indirectly through autophagy. In this review, we summarize recent advances in our understanding of the reciprocal regulation of mTORC1 and primary cilia. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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24 pages, 2225 KiB

Open AccessReview

Nuclear Functions of TOR: Impact on Transcription and the Epigenome

by R. Nicholas Laribee and Ronit Weisman

Genes 2020, 11(6), 641; https://doi.org/10.3390/genes11060641 - 10 Jun 2020

Cited by 26 | Viewed by 6519

Abstract

The target of rapamycin (TOR) protein kinase is at the core of growth factor- and nutrient-dependent signaling pathways that are well-known for their regulation of metabolism, growth, and proliferation. However, TOR is also involved in the regulation of gene expression, genomic and epigenomic [...] Read more.

The target of rapamycin (TOR) protein kinase is at the core of growth factor- and nutrient-dependent signaling pathways that are well-known for their regulation of metabolism, growth, and proliferation. However, TOR is also involved in the regulation of gene expression, genomic and epigenomic stability. TOR affects nuclear functions indirectly through its activity in the cytoplasm, but also directly through active nuclear TOR pools. The mechanisms by which TOR regulates its nuclear functions are less well-understood compared with its cytoplasmic activities. TOR is an important pharmacological target for several diseases, including cancer, metabolic and neurological disorders. Thus, studies of the nuclear functions of TOR are important for our understanding of basic biological processes, as well as for clinical implications. Full article

(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)

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