scholarly journals Protein Acetylation Induced by Dichloroacetate (DCA) Treatment is Associated with Decreased Respiration in Cultured Hepatocytes: Preliminary Results

2019 ◽  
Author(s):  
Jesse G. Meyer
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Physiological Role ◽  
Pyruvate Dehydrogenase Kinase ◽  
Protein Acetylation ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Excess Production ◽  
Lysine Residues ◽  
Genetic Perturbations

AbstractProtein post-translational modification (PTM) by acetylation at the ε-amine on lysine residues in proteins regulates various cellular processes including transcription and metabolism. Several metabolic and genetic perturbations are known to increase acetylation of various proteins. Hyper-acetylation can also be induced using deacetylase inhibitors. While there is much interest in discovering drugs that can reverse protein acetylation, pharmacological tools that increase non-enzymatic protein acetylation are needed in order to understand the physiological role of excess protein acetylation. In this study, I assessed whether inhibition of pyruvate dehydrogenase kinase (PDHK) could cause protein hyper-acetylation due to excess production of acetyl-CoA by pyruvate dehydrogenase (PDH). Western blot of total protein from dichloroacetate (DCA) treated hepatocytes with anti-acetyl-lysine antibody showed increased protein acetylation, and seahorse respirometry of DCA pretreated hepatocytes indicated a subtle decrease in basal and maximal respiratory capacity.

scholarly journals Acetylproteomics analyses reveal critical features of lysine-ε-acetylation in Arabidopsis and a role of 14-3-3 protein acetylation in alkaline response

2022 ◽  
Vol 2 (1) ◽  
Author(s):  
Jianfei Guo ◽  
Xiaoqiang Chai ◽  
Yuchao Mei ◽  
Jiamu Du ◽  
Haining Du ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Alkaline Stress ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Post Translational Modification ◽  
Evolutionarily Conserved ◽  
Lysine Residues ◽  
Protein Lysine Acetylation ◽  
Subsequent Activation

AbstractLysine-ε-acetylation (Kac) is a post-translational modification (PTM) that is critical for metabolic regulation and cell signaling in mammals. However, its prevalence and importance in plants remain to be determined. Employing high-resolution tandem mass spectrometry, we analyzed protein lysine acetylation in five representative Arabidopsis organs with 2 ~ 3 biological replicates per organ. A total of 2887 Kac proteins and 5929 Kac sites were identified. This comprehensive catalog allows us to analyze proteome-wide features of lysine acetylation. We found that Kac proteins tend to be more uniformly expressed in different organs, and the acetylation status exhibits little correlation with the gene expression level, indicating that acetylation is unlikely caused by stochastic processes. Kac preferentially targets evolutionarily conserved proteins and lysine residues, but only a small percentage of Kac proteins are orthologous between rat and Arabidopsis. A large portion of Kac proteins overlap with proteins modified by other PTMs including ubiquitination, SUMOylation and phosphorylation. Although acetylation, ubiquitination and SUMOylation all modify lysine residues, our analyses show that they rarely target the same sites. In addition, we found that “reader” proteins for acetylation and phosphorylation, i.e., bromodomain-containing proteins and GRF (General Regulatory Factor)/14-3-3 proteins, are intensively modified by the two PTMs, suggesting that they are main crosstalk nodes between acetylation and phosphorylation signaling. Analyses of GRF6/14-3-3λ reveal that the Kac level of GRF6 is decreased under alkaline stress, suggesting that acetylation represses plant alkaline response. Indeed, K56ac of GRF6 inhibits its binding to and subsequent activation of the plasma membrane H+-ATPase AHA2, leading to hypersensitivity to alkaline stress. These results provide valuable resources for protein acetylation studies in plants and reveal that protein acetylation suppresses phosphorylation output by acetylating GRF/14-3-3 proteins.

scholarly journals Interphotoreceptor coupling: an evolutionary perspective

2021 ◽  
Author(s):  
Lorenzo Cangiano ◽  
Sabrina Asteriti
Keyword(s):  
Visual Information ◽  
Signal To Noise Ratio ◽  
Electrical Coupling ◽  
Physiological Role ◽  
Cellular Processes ◽  
Contact Points ◽  
Highly Sensitive ◽  
The Many ◽  
The Impact

AbstractIn the vertebrate retina, signals generated by cones of different spectral preference and by highly sensitive rod photoreceptors interact at various levels to extract salient visual information. The first opportunity for such interaction is offered by electrical coupling of the photoreceptors themselves, which is mediated by gap junctions located at the contact points of specialised cellular processes: synaptic terminals, telodendria and radial fins. Here, we examine the evolutionary pressures for and against interphotoreceptor coupling, which are likely to have shaped how coupling is deployed in different species. The impact of coupling on signal to noise ratio, spatial acuity, contrast sensitivity, absolute and increment threshold, retinal signal flow and colour discrimination is discussed while emphasising available data from a variety of vertebrate models spanning from lampreys to primates. We highlight the many gaps in our knowledge, persisting discrepancies in the literature, as well as some major unanswered questions on the actual extent and physiological role of cone-cone, rod-cone and rod-rod communication. Lastly, we point toward limited but intriguing evidence suggestive of the ancestral form of coupling among ciliary photoreceptors.

Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

2018 ◽  
Vol 25 (1) ◽  
pp. 5-21 ◽  
Author(s):  
Ylenia Cau ◽  
Daniela Valensin ◽  
Mattia Mori ◽  
Sara Draghi ◽  
Maurizio Botta
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Specific Protein ◽  
Protein Protein Interactions ◽  
Cellular Processes ◽  
Protein Partners ◽  
High Sequence Homology ◽  
Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

SUBSTANTIATION OF NECESSITY OF APPLICATION OF PHOSPHOLIPIDS IN THE PRODUCTION OF FUNCTIONAL FOODSTUFFS

2018 ◽  
Author(s):  
Н.Н. КОРНЕН ◽  
С.А. КАЛМАНОВИЧ ◽  
Т.А. ШАХРАЙ ◽  
Е.П. ВИКТОРОВА
Keyword(s):  
Nutritional Status ◽  
Dietary Supplements ◽  
Physiological Role ◽  
Regulatory Function ◽  
Medical Sciences ◽  
Cellular Processes ◽  
Level Of Knowledge ◽  
Protective Fabrics ◽  
Technological University

Проведен анализ современных научных представлений о роли фосфолипидов (ФЛ) в обеспечении функционирования биомембран и их регуляторной функции в важнейших клеточных процессах. Из ФЛ состоит 50% печени, 1/3 мозговых изолирующих и защитных тканей, окружающих головной и спинной мозг. По рекомендациям РАМН, физиологическая потребность взрослого человека в ФЛ составляет 5–7 г/сут. Согласно проведенным исследованиям, в пищевом статусе населения РФ дефицит ФЛ составляет от 50 до 80%. Показано, что современный уровень знаний о физиологической роли ФЛ способствует созданию и внедрению в производство фосфолипидных продуктов на основе ФЛ и фосфолипидных БАД на основе растительных лецитинов, употребление которых может нормализовать пищевой статус. Дано описание фосфолипидных продуктов и БАД серии Тонус (Супер-Тонус, Фито-Тонус, Тонус-Плюс) и серии Витол (Витол, Витол-Холин и Витол-ФЭИ), разработанных учеными Кубанского государственного технологического университета. Показаны возможности применения растительных лецитинов, фосфолипидных продуктов и БАД на их основе в качестве многофункциональных рецептурных компонентов при производстве пищевых продуктов функционального и специализированного назначения. The analysis of modern scientific ideas about the role of phospholipids (FL) in ensuring the functioning of biomembranes and their regulatory function in the most important cellular processes is carried out. So, 50% of a liver, 1/3 brain isolating and protective fabrics surrounding a brain and spinal cord consist of FL. According to the recommendations of the Russian Academy of Medical Sciences, the physiological need of an adult in FL is 5–7 g/day. According to the conducted studies, in the nutritional status of the Russian population, the deficit of FL is from 50 to 80%. It is shown that the current level of knowledge about the physiological role of FL contributes to the creation and introduction of phospholipid products based on FL and phospholipid supplements on the basis of vegetable lecithins, the use of which can normalize the nutritional status. The description of phospholipid products and dietary supplements developed by scientists of the Kuban State Technological University of the Tonus series (Super Tonus, Phyto Tonus, Tonus Plus) and the Vitol series (Vitol, Vitol Kholin and Vitol FEI) is given. The possibilities of using vegetable lecithins, phospholipid products and dietary supplements on their basis are shown as multifunctional prescription components in the production of functional and specialized food products.

Functional analysis of the SUMOylation pathway in Drosophila

2008 ◽  
Vol 36 (5) ◽  
pp. 868-873 ◽  
Author(s):  
Ana Talamillo ◽  
Jonatan Sánchez ◽  
Rosa Barrio
Keyword(s):  
Functional Analysis ◽  
Fine Tuning ◽  
Model Systems ◽  
Post Translational Modification ◽  
Reversible Process ◽  
Cellular Processes ◽  
Tuning Mechanism ◽  
Sumo Conjugation

SUMOylation, a reversible process used as a ‘fine-tuning’ mechanism to regulate the role of multiple proteins, is conserved throughout evolution. This post-translational modification affects several cellular processes by the modulation of subcellular localization, activity or stability of a variety of substrates. A growing number of proteins have been identified as targets for SUMOylation, although, for many of them, the role of SUMO conjugation on their function is unknown. The use of model systems might facilitate the study of SUMOylation implications in vivo. In the present paper, we have compiled what is known about SUMOylation in Drosophila melanogaster, where the use of genetics provides new insights on SUMOylation's biological roles.

Abstract MP204: Pyruvate Dehydrogenase Kinase Isozyme Specific Regulation Of Protein Acetylation In Cardiac Tissue

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Chae-Myeong Ha ◽  
Adam R Wende
Keyword(s):  
Gene Expression ◽  
Heart Disease ◽  
Knockout Mice ◽  
Pyruvate Dehydrogenase ◽  
Cardiac Tissue ◽  
Cell Protein ◽  
Protein Acetylation ◽  
Acetyl Coa ◽  
The Impact

Heart disease is the number one cause of death in developed countries. Metabolic diseases influence the severity of heart disease linked to risk factors which are thought to alter epigenetic mechanisms. Pyruvate dehydrogenase (PDH) kinases (PDK), which phosphorylate and reduce the activity of PDH the nexus of glucose oxidation and fatty acid oxidation are sensitive to metabolic status. Four isozymes of PDK (PDK1-4) exist with PDK2 and PDK4 as the major regulators in cardiac tissue. Owing to the role of PDH in regulating pyruvate to acetyl-CoA, we hypothesized that PDK inhibition may regulate protein acetylation through increasing acetyl-CoA because of PDH activation leading to post-translational modifications both directly to proteins in metabolic pathways as well as to histones associated with the genes encoding them. To test this, we utilized PDK2 germline knockout mice (P2KO), PDK4 germline knockout mice (P4KO), and PDK2 and PDK4 double knockout (DKO) mice for molecular analysis. Our results identify a novel increase in whole-cell protein acetylation in P2KO left ventricle tissue (LV). However, protein acetylation in P4KO LV was not changed compared to WT mice. The most robust protein acetylation was observed in the DKO LV. Furthermore, when we explored sub-cellular distribution of protein acetylation, the greatest increases were found on cytoplasmic proteins, with moderate changes in mitochondrial proteins. We also found PDK2 ablation induces histone H3 acetylation, which may also lead to changes in gene expression. Moreover, this protein acetylation in P2KO and DKO was not seen in other tissues examined (e.g., liver, skeletal muscle). The hyperacetylation is robust in male LV compared to female LV. In conclusion, our study supports a novel protein acetylation mechanism that is both tissue and PDK isozyme specific highlighting the role of PDK2, which is relatively understudied compared to PDK4 in heart disease. Further study will evaluate if the hyperacetylation has a beneficial effect in various heart disease settings as well as identify the impact on changes in gene expression. This study supports PDK isozyme-specific inhibition strategies will be required to develop therapeutic targets of cardiovascular disease with metabolic inflexibility.

scholarly journals Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1731 ◽  
Author(s):  
Carina Neitzel ◽  
Philipp Demuth ◽  
Simon Wittmann ◽  
Jörg Fahrer
Keyword(s):  
Colorectal Cancer ◽  
Energy Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Dietary Factors ◽  
Pyruvate Dehydrogenase Kinase ◽  
Driver Mutations ◽  
The Tca Cycle

Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

scholarly journals FOXO3a is stabilized by USP18-mediated de-ISGylation and inhibits TGF-β1-induced fibronectin expression

2019 ◽  
Vol 68 (3) ◽  
pp. 786-791 ◽  
Author(s):  
Ban Wang ◽  
Yanhui Li ◽  
Heather Wang ◽  
Jing Zhao ◽  
Yutong Zhao ◽  
...  
Keyword(s):  
Half Life ◽  
Transforming Growth Factor ◽  
Fibroblast Cells ◽  
Post Translational Modification ◽  
Human Lung Fibroblast ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Fibronectin Expression ◽  
Tgf Β1

FOXO3a belongs to a family of transcription factors characterized by a conserved forkhead box DNA-binding domain. It has been known to regulate various cellular processes including cell proliferation, apoptosis and differentiation. Post-translational modifications of FOXO3a and their roles in the regulation of FOXO3a activity have been well-documented. FOXO3a can be phosphorylated, acetylated and ubiquitinated, however, the ISGylation of FOXO3a has not been reported. Protein overexpression, ISGylation and half-life were measured to determine the post-translational modification of FOXO3a. Human fibroblast cells were treated with transforming growth factor (TGF)-β1 to determine the role of FOXO3a ISGylation in TGF-β1 signaling. FOXO3a’s half-life is around 3.7 hours. Inhibition of the proteasome, not lysosome, extends its half-life. ISGylation, but not ubiquitination of FOXO3a, is increased in the presence of the proteasome inhibitor. Overexpression of ISG15 increases FOXO3a degradation, while overexpression of USP18 stabilizes FOXO3a through de-ISGylation. These results suggest that FOXO3a is degraded in the ISGylation and proteasome system, which can be reversed by USP18, an ISG15-specific deubiquitinase. This study reveals a new molecular mechanism by which ISGylation regulates FOXO3a degradation. Furthermore, we show that the overexpression of FOXO3a attenuated TGF-β1-induced fibronectin expression in human lung fibroblast cells without altering Smad2/3 expression and activation. FOXO3a can be ISGylated, which can regulate FOXO3a stability. USP18/FOXO3a pathway is a potential target for treating TGF-β1-mediated fibrotic diseases such as idiopathic pulmonary fibrosis.

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