Plants respond to low-nutrient conditions through metabolic and morphology changes that increase their ability to survive and grow. The transcription factor RAP2.11 was identified as a component in the response to low...Plants respond to low-nutrient conditions through metabolic and morphology changes that increase their ability to survive and grow. The transcription factor RAP2.11 was identified as a component in the response to low potassium through regulation of the high-affinity K＋ uptake transporter AtHAK5 and other components of the low- potassium signal transduction pathway. RAP2.11 was identified through the activation tagging of Arabidopsis lines that contained a luciferase marker driven by the AtHAK5 promoter that is normally only induced by low potassium. This factor bound to a GCC-box of the AtHAK5 promoter in vitro and in vivo. Transcript profiling revealed that a large number of genes were up-regulated in roots by RAP2.11 overexpression. Many regulated genes were identified to be in functional cate- gories that are important in Iow-K＋ signaling. These categories included ethylene signaling, reactive oxygen species pro- duction, and calcium signaling. Promoter regions of the up-regulated genes were enriched in the GCCGGC motif also contained in the AtHAK5 promoter. These results suggest that RAP2.11 regulates AtHAK5 expression under Iow-K＋ con- ditions and also contributes to a coordinated response to low-potassium conditions through the regulation of other genes in the Iow-K＋ signaling cascade.展开更多
BACKGROUND： The protein kinase Target Of Rapamycin （TOR） is a nexus for the regulation of eukaryotic cell growth. TOR assembles into one of two distinct signalling complexes, TOR complex 1 （TORC1） and TORC2 （mTO...BACKGROUND： The protein kinase Target Of Rapamycin （TOR） is a nexus for the regulation of eukaryotic cell growth. TOR assembles into one of two distinct signalling complexes, TOR complex 1 （TORC1） and TORC2 （mTORC1/2 in mammals）, with a set of largely non-overlapping protein partners. （m）TORC 1 activation occurs in response to a series of stimuli relevant to cell growth, including nutrient availability, growth factor signals and stress, and regulates much of the cell＇s biosynthetic activity, from proteins to lipids, and recycling through autophagy, mTORC1 regulation is of great therapeutic significance, since in humans many of these signalling complexes, alongside subunits of mTORC1 itself, are implicated in a wide variety of pathophysiologies, including multiple types of cancer, neurological disorders, neurodegenerative diseases and metabolic disorders including diabetes. METHODOLOGY： Recent years have seen numerous structures determined of （m）TOR, which have provided mechanistic insight into （m）TORC 1 activation in particular, however the integration of cellular signals occurs upstream of the kinase and remains incompletely understood. Here we have collected and analysed in detail as many as possible of the molecular and structural studies which have shed light on （m）TORC 1 repression, activation and signal integration. CONCLUSIONS： A molecular understanding of this signal integration pathway is required to understand how （m）TORC1 activation is reconciled with the many diverse and contradictory stimuli affecting cell growth. We discuss the current level of molecular understanding of the upstream components of the （m）TORC1 signalling pathway, recent progress on this key biochemical frontier, and the future studies necessary to establish a mechanistic understanding of this master-switch for eukaryotic cell growth.展开更多
Nutrient sensing pathways and their regulation grant cells control over their metabolism and growth in response to changing nutrients. Factors that regulate nutrient sensing can also modulate longevity. Reduced activi...Nutrient sensing pathways and their regulation grant cells control over their metabolism and growth in response to changing nutrients. Factors that regulate nutrient sensing can also modulate longevity. Reduced activity of nutrient sensing pathways such as glucose-sensing PKA, nitrogen-sensing TOR and S6 kinase homolog Sch9 have been linked to increased life span in the yeast, Saccharomyces cerevisiae, and higher eukaryotes. Recently, reduced activity of amino acid sensing SPS pathway was also shown to increase yeast life span. Life span extension by reduced SPS activity requires enhanced NAD＋ （nicotinamide adenine dinucleotide, oxidized form） and nicotinamide riboside （NR, a NAD＋ precursor） homeostasis. Maintaining adequate NAD＋ pools has been shown to play key roles in life span extension, but factors regulating NAD＋ metabolism and homeostasis are not completely understood. Recently, NAD＋ metabolism was also linked to the phosphate （Pi）-sensing PHO pathway in yeast. Canonical PHO activation requires Pi-starvation. Interestingly, NAD＋ depletion without Pi-starvation was sufficient to induce PHO activation, increasing NR production and mobilization. Moreover, SPS signaling appears to function in parallel with PHO signaling components to regulate NR/NAD＋ homeostasis. These studies suggest that NAD＋ metabolism is likely controlled by and/or coordinated with multiple nutrient sensing pathways. Indeed, cross-regulation of PHO, PKA, TOR and Sch9 pathways was reported to potentially affect NAD＋ metabolism; though detailed mechanisms remain unclear. This review discusses yeast longevity- related nutrient sensing pathways and possible mechanisms of life span extension, regulation of NAD＋ homeostasis, and cross-talk among nutrient sensing pathways and NAD＋ homeostasis.展开更多
Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate...Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWlISNF chromatin.remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological sigrials. The ATP-dependent SWl/SNF ing complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different m^abolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.展开更多
文摘Plants respond to low-nutrient conditions through metabolic and morphology changes that increase their ability to survive and grow. The transcription factor RAP2.11 was identified as a component in the response to low potassium through regulation of the high-affinity K＋ uptake transporter AtHAK5 and other components of the low- potassium signal transduction pathway. RAP2.11 was identified through the activation tagging of Arabidopsis lines that contained a luciferase marker driven by the AtHAK5 promoter that is normally only induced by low potassium. This factor bound to a GCC-box of the AtHAK5 promoter in vitro and in vivo. Transcript profiling revealed that a large number of genes were up-regulated in roots by RAP2.11 overexpression. Many regulated genes were identified to be in functional cate- gories that are important in Iow-K＋ signaling. These categories included ethylene signaling, reactive oxygen species pro- duction, and calcium signaling. Promoter regions of the up-regulated genes were enriched in the GCCGGC motif also contained in the AtHAK5 promoter. These results suggest that RAP2.11 regulates AtHAK5 expression under Iow-K＋ con- ditions and also contributes to a coordinated response to low-potassium conditions through the regulation of other genes in the Iow-K＋ signaling cascade.
文摘BACKGROUND： The protein kinase Target Of Rapamycin （TOR） is a nexus for the regulation of eukaryotic cell growth. TOR assembles into one of two distinct signalling complexes, TOR complex 1 （TORC1） and TORC2 （mTORC1/2 in mammals）, with a set of largely non-overlapping protein partners. （m）TORC 1 activation occurs in response to a series of stimuli relevant to cell growth, including nutrient availability, growth factor signals and stress, and regulates much of the cell＇s biosynthetic activity, from proteins to lipids, and recycling through autophagy, mTORC1 regulation is of great therapeutic significance, since in humans many of these signalling complexes, alongside subunits of mTORC1 itself, are implicated in a wide variety of pathophysiologies, including multiple types of cancer, neurological disorders, neurodegenerative diseases and metabolic disorders including diabetes. METHODOLOGY： Recent years have seen numerous structures determined of （m）TOR, which have provided mechanistic insight into （m）TORC 1 activation in particular, however the integration of cellular signals occurs upstream of the kinase and remains incompletely understood. Here we have collected and analysed in detail as many as possible of the molecular and structural studies which have shed light on （m）TORC 1 repression, activation and signal integration. CONCLUSIONS： A molecular understanding of this signal integration pathway is required to understand how （m）TORC1 activation is reconciled with the many diverse and contradictory stimuli affecting cell growth. We discuss the current level of molecular understanding of the upstream components of the （m）TORC1 signalling pathway, recent progress on this key biochemical frontier, and the future studies necessary to establish a mechanistic understanding of this master-switch for eukaryotic cell growth.
文摘Nutrient sensing pathways and their regulation grant cells control over their metabolism and growth in response to changing nutrients. Factors that regulate nutrient sensing can also modulate longevity. Reduced activity of nutrient sensing pathways such as glucose-sensing PKA, nitrogen-sensing TOR and S6 kinase homolog Sch9 have been linked to increased life span in the yeast, Saccharomyces cerevisiae, and higher eukaryotes. Recently, reduced activity of amino acid sensing SPS pathway was also shown to increase yeast life span. Life span extension by reduced SPS activity requires enhanced NAD＋ （nicotinamide adenine dinucleotide, oxidized form） and nicotinamide riboside （NR, a NAD＋ precursor） homeostasis. Maintaining adequate NAD＋ pools has been shown to play key roles in life span extension, but factors regulating NAD＋ metabolism and homeostasis are not completely understood. Recently, NAD＋ metabolism was also linked to the phosphate （Pi）-sensing PHO pathway in yeast. Canonical PHO activation requires Pi-starvation. Interestingly, NAD＋ depletion without Pi-starvation was sufficient to induce PHO activation, increasing NR production and mobilization. Moreover, SPS signaling appears to function in parallel with PHO signaling components to regulate NR/NAD＋ homeostasis. These studies suggest that NAD＋ metabolism is likely controlled by and/or coordinated with multiple nutrient sensing pathways. Indeed, cross-regulation of PHO, PKA, TOR and Sch9 pathways was reported to potentially affect NAD＋ metabolism; though detailed mechanisms remain unclear. This review discusses yeast longevity- related nutrient sensing pathways and possible mechanisms of life span extension, regulation of NAD＋ homeostasis, and cross-talk among nutrient sensing pathways and NAD＋ homeostasis.
基金This work was supported by the National Natural Science Foundation of China （Grant No. 81670740）, the Thousand Young Talents Plan of China, and the National Key Research and Development Programme of China （No. 2016YFC1305303） to Z.X.M. by National Natural Science Foundation of China （Grant Nos. 81570759 and 81270938）, National Key Research and Development Programme of China （No. 2016YFC1305301）, Zhejiang Provincial Key Science and Technol- ogy Project （No. 2014C03045-2）, Key Disciplines of Medicine （Innovation discipline,11-CX24） to J.F. and by NIH grant （No. DKl12800） to J.D.L.
文摘Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWlISNF chromatin.remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological sigrials. The ATP-dependent SWl/SNF ing complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different m^abolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.
