scholarly journals Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses

PLoS Biology ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. e3000981
Author(s):  
Ryan Houston ◽  
Shiori Sekine ◽  
Michael J. Calderon ◽  
Fayaz Seifuddin ◽  
Guanghui Wang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Histone Deacetylases ◽  
Culture Media ◽  
Lipid Synthesis ◽  
Essential Element ◽  
Cell System ◽  
Acetyl Coa ◽  
Atp Production ◽  
Wide Range ◽  
A Cell

The metabolite acetyl-coenzyme A (acetyl-CoA) serves as an essential element for a wide range of cellular functions including adenosine triphosphate (ATP) production, lipid synthesis, and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa histone deacetylases (HDACs). Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.

scholarly journals Acetylation-mediated phase control of the nucleolus regulates cellular acetyl-CoA responses

2020 ◽  
Author(s):  
Ryan Houston ◽  
Shiori Sekine ◽  
Michael J. Calderon ◽  
Fayaz Seifuddin ◽  
Guanghui Wang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Culture Media ◽  
Lipid Synthesis ◽  
Essential Element ◽  
Cell System ◽  
Cellular Functions ◽  
Acetyl Coa ◽  
Atp Production ◽  
Wide Range ◽  
A Cell

SummaryThe metabolite acetyl-CoA serves as an essential element for a wide range of cellular functions including ATP production, lipid synthesis and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using CRISPR-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa HDAC deacetylases regulating the phase state of the nucleolus. Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.

Mechanisms of cholesterol synthesis inhibition by D-glucosamine

1985 ◽  
Vol 63 (12) ◽  
pp. 1253-1257 ◽  
Author(s):  
Susan J. Friedman ◽  
Stanley Cheng ◽  
Philip Skehan
Keyword(s):  
Cholesterol Biosynthesis ◽  
Lipid Synthesis ◽  
Amino Sugar ◽  
Sterol Synthesis ◽  
Cholesteryl Esters ◽  
Acetate Incorporation ◽  
Glial Tumor ◽  
Acetyl Coa ◽  
Wide Range ◽  
Acetate Utilization

The amino sugar D-glucosamine possesses antitumor activity which is thought to depend in part upon its ability to impair cholesterol biosynthesis and damage cellular membranes. The present study examined the effect of glucosamine on acetate utilization for lipid and sterol synthesis in rat C6 glial tumor cells. At cytotoxic concentrations, the amino sugar inhibited [14C]acetate incorporation into nonesterified sterols and lipids but increased the flow of label into cholesteryl esters. A comparison of the rates of acetate utilization for glucosamine metabolism (N-acetylation) and sterol and lipid synthesis suggested that glucosamine might act by competing for a common cytosolic pool of acetyl CoA. The inhibition of lipid and sterol synthesis, however, remained constant over a wide range of extracellular acetate concentrations. These results suggest that, if glucosamine acts by restricting the supply of acetate for these biosynthetic processes, it probably inhibits a step prior to the formation of acetyl CoA. Alternative mechanisms are discussed.

scholarly journals Phosphate in Virulence of Candida albicans and Candida glabrata

2020 ◽  
Vol 6 (2) ◽  
pp. 40 ◽  
Author(s):  
Julia R. Köhler ◽  
Maikel Acosta-Zaldívar ◽  
Wanjun Qi
Keyword(s):  
Stress Responses ◽  
Drug Targets ◽  
Fungal Pathogens ◽  
Essential Element ◽  
Close Relative ◽  
Pho Regulon ◽  
Phosphate Homeostasis ◽  
Yeast Saccharomyces Cerevisiae ◽  
Atp Production ◽  
Novel Drug

Candida species are the most commonly isolated invasive human fungal pathogens. A role for phosphate acquisition in their growth, resistance against host immune cells, and tolerance of important antifungal medications is becoming apparent. Phosphorus is an essential element in vital components of the cell, including chromosomes and ribosomes. Producing the energy currency of the cell, ATP, requires abundant inorganic phosphate. A comparison of the network of regulators and effectors that controls phosphate acquisition and intracellular distribution, the PHO regulon, between the model yeast Saccharomyces cerevisiae, a plant saprobe, its evolutionarily close relative C. glabrata, and the more distantly related C. albicans, highlights the need to coordinate phosphate homeostasis with adenylate biosynthesis for ATP production. It also suggests that fungi that cope with phosphate starvation as they invade host tissues, may link phosphate acquisition to stress responses as an efficient mechanism of anticipatory regulation. Recent work indicates that connections among the PHO regulon, Target of Rapamycin Complex 1 signaling, oxidative stress management, and cell wall construction are based both in direct signaling links, and in the provision of phosphate for sufficient metabolic intermediates that are substrates in these processes. Fundamental differences in fungal and human phosphate homeostasis may offer novel drug targets.

scholarly journals The role of sirtuins in cardiac disease

2015 ◽  
Vol 309 (9) ◽  
pp. H1375-H1389 ◽  
Author(s):  
Shouji Matsushima ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Mating Type ◽  
Stress Responses ◽  
Histone Deacetylases ◽  
Class Iii ◽  
Beneficial Effects ◽  
Damage Repair ◽  
Wide Range ◽  
Apoptosis And Inflammation

Modification of histones is one of the important mechanisms of epigenetics, in which genetic control is determined by factors other than an individual's DNA sequence. Sirtuin family proteins, which are class III histone deacetylases, were originally identified as gene silencers that affect the mating type of yeast, leading to the name “silent mating-type information regulation 2” (SIR2). They are characterized by their requirement of nicotinamide adenine dinucleotide for their enzyme activity, unlike other classes of histone deacetylases. Sirtuins have been traditionally linked to longevity and the beneficial effects of calorie restriction and DNA damage repair. Recently, sirtuins have been shown to be involved in a wide range of physiological and pathological processes, including aging, energy responses to low calorie availability, and stress resistance, as well as apoptosis and inflammation. Sirtuins can also regulate mitochondrial biogenesis and circadian clocks. Seven sirtuin family proteins (Sirt1-7) have been identified as mammalian SIR2 orthologs, localized in different subcellular compartments, namely, the cytoplasm (Sirt1, 2), the mitochondria (Sirt3, 4, 5), and the nucleus (Sirt1, 2, 6, 7). Sirt1 is evolutionarily close to yeast SIR2 and has been the most intensively investigated in the cardiovascular system. Endogenous Sirt1 plays a pivotal role in mediating the cell death/survival process and has been implicated in the pathogenesis of cardiovascular disease. Downregulation of Sirt2 is protective against ischemic-reperfusion injury. Increased Sirt3 expression has been shown to correlate with longevity in humans. In addition, Sirt3 protects cardiomyocytes from aging and oxidative stress and suppresses cardiac hypertrophy. Sirt6 has also recently been demonstrated to attenuate cardiac hypertrophy, and Sirt7 is known to regulate apoptosis and stress responses in the heart. On the other hand, the roles of Sirt4 and Sirt5 in the heart remain largely uncharacterized.

scholarly journals Cyclic AMP effects on cell-to-cell junctional membrane permeability during adipocyte differentiation of 3T3-L1 fibroblasts.

1985 ◽  
Vol 100 (1) ◽  
pp. 265-269 ◽  
Author(s):  
R Azarnia ◽  
T R Russell
Keyword(s):  
Cyclic Amp ◽  
Electrical Coupling ◽  
Cell Communication ◽  
Lipid Synthesis ◽  
Cell System ◽  
Dibutyryl Cyclic Amp ◽  
Junctional Permeability ◽  
Adipose Conversion ◽  
A Cell

Mouse 3T3-L1 fibroblast cells, also know as preadipocytes, differentiate in vitro into adipocytes when treated with promoting agents and acquire numerous properties characteristic of mature fat cells. We studied junctional cell-to-cell communication by measuring the incidence of electrical coupling and transfer of carboxy-fluorescein among these cells. When 3T3-L1 cells were induced to differentiate into adipocytes, they lost virtually all cell-cell communication. Preadipocytes that remained nondifferentiated after the treatment maintained normal communication. Loss of communication in the adipocytes invariably coincided with appearance of lipid droplets and not with other phenotypic changes. In the differentiating cells, loss of cell-to-cell communication and lipid accumulation was prevented if dibutyryl cyclic AMP and caffeine were present in the culture medium. Addition of dibutyryl cyclic AMP and caffeine to already differentiated adipocytes resulted in loss of lipid and simultaneously improved junctional permeability. The results demonstrate that in the in vitro 3T3-L1 cell system, (a) cell-to-cell communication and lipid synthesis are intimately related during the adipose conversion and (b) cAMP affects the expression of the two phenotypes.

scholarly journals Reciprocal Regulation of AMPK/SNF1 and Protein Acetylation

2018 ◽  
Vol 19 (11) ◽  
pp. 3314 ◽  
Author(s):  
Ales Vancura ◽  
Shreya Nagar ◽  
Pritpal Kaur ◽  
Pengli Bu ◽  
Madhura Bhagwat ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Adenosine Monophosphate ◽  
Cellular Level ◽  
Yeast Cells ◽  
Protein Acetylation ◽  
Acetyl Coa ◽  
Reciprocal Regulation ◽  
Atp Production ◽  
Upstream Kinase

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) serves as an energy sensor and master regulator of metabolism. In general, AMPK inhibits anabolism to minimize energy consumption and activates catabolism to increase ATP production. One of the mechanisms employed by AMPK to regulate metabolism is protein acetylation. AMPK regulates protein acetylation by at least five distinct mechanisms. First, AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC) and thus regulates acetyl-CoA homeostasis. Since acetyl-CoA is a substrate for all lysine acetyltransferases (KATs), AMPK affects the activity of KATs by regulating the cellular level of acetyl-CoA. Second, AMPK activates histone deacetylases (HDACs) sirtuins by increasing the cellular concentration of NAD+, a cofactor of sirtuins. Third, AMPK inhibits class I and II HDACs by upregulating hepatic synthesis of α-hydroxybutyrate, a natural inhibitor of HDACs. Fourth, AMPK induces translocation of HDACs 4 and 5 from the nucleus to the cytoplasm and thus increases histone acetylation in the nucleus. Fifth, AMPK directly phosphorylates and downregulates p300 KAT. On the other hand, protein acetylation regulates AMPK activity. Sirtuin SIRT1-mediated deacetylation of liver kinase B1 (LKB1), an upstream kinase of AMPK, activates LKB1 and AMPK. AMPK phosphorylates and inactivates ACC, thus increasing acetyl-CoA level and promoting LKB1 acetylation and inhibition. In yeast cells, acetylation of Sip2p, one of the regulatory β-subunits of the SNF1 complex, results in inhibition of SNF1. This results in activation of ACC and reduced cellular level of acetyl-CoA, which promotes deacetylation of Sip2p and activation of SNF1. Thus, in both yeast and mammalian cells, AMPK/SNF1 regulate protein acetylation and are themselves regulated by protein acetylation.

scholarly journals Toxin Production in Soybean (Glycine max L.) Plants with Charcoal Rot Disease and by Macrophomina phaseolina, the Fungus that Causes the Disease

Toxins ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 645 ◽  
Author(s):  
Hamed K. Abbas ◽  
Nacer Bellaloui ◽  
Cesare Accinelli ◽  
James R. Smith ◽  
W. Thomas Shier
Keyword(s):  
Culture Media ◽  
Leaf Disc ◽  
Toxin Production ◽  
Macrophomina Phaseolina ◽  
Economic Losses ◽  
Limit Of Quantification ◽  
Charcoal Rot ◽  
Wide Range ◽  
Soybean Plants ◽  
Rot Disease

Charcoal rot disease, caused by the fungus Macrophomina phaseolina, results in major economic losses in soybean production in southern USA. M. phaseolina has been proposed to use the toxin (-)-botryodiplodin in its root infection mechanism to create a necrotic zone in root tissue through which fungal hyphae can readily enter the plant. The majority (51.4%) of M. phaseolina isolates from plants with charcoal rot disease produced a wide range of (-)-botryodiplodin concentrations in a culture medium (0.14–6.11 µg/mL), 37.8% produced traces below the limit of quantification (0.01 µg/mL), and 10.8% produced no detectable (-)-botryodiplodin. Some culture media with traces or no (-)-botryodiplodin were nevertheless strongly phytotoxic in soybean leaf disc cultures, consistent with the production of another unidentified toxin(s). Widely ranging (-)-botryodiplodin levels (traces to 3.14 µg/g) were also observed in the roots, but not in the aerial parts, of soybean plants naturally infected with charcoal rot disease. This is the first report of (-)-botryodiplodin in plant tissues naturally infected with charcoal rot disease. No phaseolinone was detected in M. phaseolina culture media or naturally infected soybean tissues. These results are consistent with (-)-botryodiplodin playing a role in the pathology of some, but not all, M. phaseolina isolates from soybeans with charcoal rot disease in southern USA.

scholarly journals Effect of RIP Overexpression on Abiotic Stress Tolerance and Development of Rice

2021 ◽  
Vol 22 (3) ◽  
pp. 1434
Author(s):  
Pieter Wytynck ◽  
Jeroen Lambin ◽  
Simin Chen ◽  
Sinem Demirel Asci ◽  
Isabel Verbeke ◽  
...  
Keyword(s):  
Methyl Jasmonate ◽  
Stress Responses ◽  
Abiotic Stress Tolerance ◽  
Protein Translation ◽  
Ribosome Inactivating Proteins ◽  
Close Proximity ◽  
Inhibit Protein Translation ◽  
Plant Ribosomes ◽  
A Cell ◽  
Type 3

Ribosome-inactivating proteins (RIPs) are a class of cytotoxic enzymes that can inhibit protein translation by depurinating rRNA. Most plant RIPs are synthesized with a leader sequence that sequesters the proteins to a cell compartment away from the host ribosomes. However, several rice RIPs lack these signal peptides suggesting they reside in the cytosol in close proximity to the plant ribosomes. This paper aims to elucidate the physiological function of two nucleocytoplasmic RIPs from rice, in particular, the type 1 RIP referred to as OsRIP1 and a presumed type 3 RIP called nuRIP. Transgenic rice lines overexpressing these RIPs were constructed and studied for developmental effects resulting from this overexpression under greenhouse conditions. In addition, the performance of transgenic seedlings in response to drought, salt, abscisic acid and methyl jasmonate treatment was investigated. Results suggest that both RIPs can affect methyl jasmonate mediated stress responses.

scholarly journals Frequency of myelin oligodendrocyte glycoprotein antibodies in a large cohort of neurological patients

2021 ◽  
Vol 7 (2) ◽  
pp. 205521732110227
Author(s):  
Friederike Held ◽  
Sudhakar Reddy Kalluri ◽  
Achim Berthele ◽  
Ana-Katharina Klein ◽  
Markus Reindl ◽  
...  
Keyword(s):  
Time Course ◽  
Neurological Diseases ◽  
External Validation ◽  
Diagnostic Value ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Large Cohort ◽  
Wide Range ◽  
Neurological Patients ◽  
A Cell ◽  
Nosological Entity

Background Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOG-AD) is recognized as a distinct nosological entity. IgG antibodies against MOG (MOG-Ab) overlap with neuromyelitis optica spectrum disorders (NMOSD) phenotype in adults. However, an increasing number of clinical phenotypes have been reported to be associated with MOG-Ab. Objective To investigate the seroprevalence of MOG-Ab under consideration of demographics, disease entities and time course in a large cohort of unselected neurological patients. Methods Blood samples of 2.107 consecutive adult neurologic patients admitted to our department between 2016-2017 were tested for MOG-Ab using a cell-based assay. MOG-Ab persistence was analyzed in follow-up samples. External validation was performed in two independent laboratories. Results We found MOG-Ab in 25 of 2.107 (1.2%) patients. High antibody ratios were mostly associated with NMOSD and MOG-AD phenotype (5/25). Low ratios occurred in a wide range of neurological diseases, predominantly in other demyelinating CNS diseases (5/25) and stroke (6/25). MOG-Ab persistence over time was not confined to NMOSD and MOG-AD phenotype. Conclusion The present study demonstrates the occurrence of MOG-Ab in a wide range of neurological diseases. Only high MOG-Ab ratios were associated with a defined clinical phenotype, but low MOG-Ab ratios were not. The diagnostic value of low MOG-Ab is thus highly limited.

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