scholarly journals Regulation of Cidea protein stability by the ubiquitin-mediated proteasomal degradation pathway

2007 ◽  
Vol 408 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Siu Chiu Chan ◽  
Sheng-Cai Lin ◽  
Peng Li
Keyword(s):  
Protein Stability ◽  
Mutational Analysis ◽  
Critical Role ◽  
Proteasome Inhibitors ◽  
Degradation Pathway ◽  
Post Translational Modification ◽  
Brown Adipocytes ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Lysine Residues

Cidea, one of three members of the CIDE (cell-death-inducing DNA-fragmentation-factor-45-like effector) family of proteins, is highly enriched in brown adipose tissue, in which it plays a critical role in adaptive thermogenesis and fat accumulation. Cidea-null mice have increased energy expenditure with resistance to high-fat-diet-induced obesity and diabetes. However, little is known as to how the Cidea protein is regulated. In the present study we show that Cidea is a short-lived protein as measured by cycloheximide-based protein chase experiments in different cell lines or in differentiated brown adipocytes. Proteasome inhibitors specifically increased the stability of both transfected and endogenous Cidea protein. Furthermore, Cidea protein was found to be polyubiquitinated when overexpressed in different culture cells as well as in differentiated mature brown adipocytes. Extensive mutational analysis of individual lysine residues revealed that ubiquitinated lysine residues are located in the N-terminal region of Cidea, as alteration of these lysine residues to alanine (N-5KA mutant) renders Cidea much more stable when compared with wild-type or C-terminal lysine-less mutant (C-5KA). Furthermore, K23 (Lys23) within the N-terminus of the Cidea was identified as the major contributor to its polyubiquitination signal and the protein instability. Taken together, the results of our study demonstrated that the ubiquitin–proteasome system confers an important post-translational modification that controls the protein stability of Cidea.

Hybrid gene therapy designed to fully understand the underlying molecular cancer process may be a feasible option

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Protein Stability ◽  
Kinase Inhibitors ◽  
Combined Therapy ◽  
Proteasome Inhibitors ◽  
Post Translational Modification ◽  
Synergistic Activation ◽  
Feasible Option ◽  
Potential Alternative ◽  
Cox 2 Inhibitors

Combination gene therapy properly tailored to a full understanding of the underlying molecular cancer process may be a possible approach. In developing malignancies, the uptake and concentration of tumor suppressors at their target locations may be controlled. As with p53, this intracellular compartmentalization can be done by modulating target gene nuclear transport via imports and exports. Mediating PTMs such as ubiquitin, phosphorylation, and dephosphorylation to impact protein location is also a feasible method. For example, proteasome inhibitors directly or indirectly enhance nuclear localization of proteasome-target proteins such MG-132 and Lactacystin in acute myeloid leukemia PTM regulation is also crucial for managing protein stability; decreased ubiquitination by NEDD8 inhibitors boosts protein stability, which improves mitochondrial localization, although COX-2 inhibitors promote p53 stability and nuclear localisation. PTMs also play a crucial function in binding DNA control. For example, N-terminal phosphorylation and other PTMs alter p53's DNA-binding affinity and selectivity. A careful balance of gene therapy, transport inhibitors, kinase inhibitors, and post-translational modification inhibitors might be a potential alternative. In combined therapy, the p53 nuclear protein displays synergistic activation by enhancing actinomycin-D kinase and inhibiting upregulated-MDM2 from binding through nutlin-3a to p53. Using PEST-NPs as gene treatments requires a pragmatic approach due to their heterogeneous cancer activity.

scholarly journals Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat

2021 ◽  
Author(s):  
Swe Mar Oo ◽  
Hein Ko Oo ◽  
Hiroaki Takayama ◽  
Takehiro Kanamori ◽  
Yumie Takeshita ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Cold Exposure ◽  
Intrinsic Factor ◽  
Serum Levels ◽  
Selenoprotein P ◽  
Brown Adipocytes ◽  
Reductive Stress ◽  
Obesity And Diabetes ◽  
Mitochondrial Ros ◽  
Brown Adipose

Abstract Reactive oxygen species (ROS) oxidize and activate the uncoupler protein 1 (UCP1) in brown adipose tissue (BAT) under physiological cold exposure and noradrenaline (NA) stimulation to increase thermogenesis. However, pathological significance and the endogenous regulator of the ROS-mediated BAT activation remain unclear. Here, we show that serum levels of selenoprotein P (SeP, encoded by Selenop) are negatively correlated with BAT activity in humans. SeP impairs UCP1 activity and thermogenesis. Physiological cold exposure downregulates Selenop in BAT. BAT-specific Selenop-deficient (BAT-Selenop KO) mice presented elevated NA-induced mitochondrial ROS production, sulfenylated UCP1, and enhanced thermogenesis and glucose uptake in BAT during cold exposure. SeP inhibits mitochondrial ROS by upregulating the expression of the antioxidant enzyme, glutathione peroxidase 4, and impairs glucose uptake in brown adipocytes. High fat/high sucrose diet upregulates Selenop in the liver and inhibits the NA-induced BAT thermogenesis in BAT-Selenop KO mice. Our data indicate that SeP, as the hepatokine and BATkine, is the first identified intrinsic factor inducing reductive stress that impairs UCP1 activation and thermogenesis in BAT, and therefore may be a potential therapeutic target for obesity and diabetes.

scholarly journals Sympathetic Transmitters Controlling Thermogenic Efficacy of Brown Adipocytes by Modulating Mitochondrial Complex V

2017 ◽  
Author(s):  
Tao-Rong Xie ◽  
Chun-Feng Liu ◽  
Jian-Sheng Kang
Keyword(s):  
Atpase Activity ◽  
Proton Leak ◽  
Mitochondrial Complex ◽  
Brown Adipocytes ◽  
Proton Atpase ◽  
Obesity Intervention ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Key Factor ◽  
New Strategies

ABSTRACTObesity is epidemic worldwide as the results of excessive energy intake or inefficient energy expenditure. It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention. However, the mechanisms controlling the efficacy of norepinephrine-induced thermogenesis in brown adipocytes remain elusive. Here, we demonstrate that the proton ATPase activity of mitochondrial complex V is a key factor, which antagonizes proton leak by UCP1 and determines the efficacy of norepinephrine-induced thermogenesis in brown adipocytes. Furthermore, to avoid unnecessary and undesired heat production, we reveal that ATP as a sympathetic cotransmitter is necessary for the high efficacy and specificity of norepinephrine-induced thermogenesis in brown adipocytes by upregulating the ATP synthase activity of complex V. Thus, we demonstrate the modulation mechanism of thermogenic efficacy in brown adipocytes. These findings imply new strategies for efficiently utilizing brown adipocytes thermogenic capacity, and therapeutic targets for the treatments of obesity and diabetes.Highlights1. Norepinephrine (NE) induces heterogeneous responses in brown adipocytes2. NE activates the H+-ATPase activity of mitochondrial complex V3. Mitochondrial complex V is a key factor in NE-induced thermogenic efficacy4. ATP as a sympathetic cotransmitter enhances the NE-induced thermogenic efficacy

scholarly journals Novel Browning Agents, Mechanisms, and Therapeutic Potentials of Brown Adipose Tissue

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Umesh D. Wankhade ◽  
Michael Shen ◽  
Hariom Yadav ◽  
Keshari M. Thakali
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Energy Homeostasis ◽  
Therapeutic Potential ◽  
Uncoupling Protein ◽  
Brown Adipocytes ◽  
Atp Production ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Beige Adipocytes

Nonshivering thermogenesis is the process of biological heat production in mammals and is primarily mediated by brown adipose tissue (BAT). Through ubiquitous expression of uncoupling protein 1 (Ucp1) on the mitochondrial inner membrane, BAT displays uncoupling of fuel combustion and ATP production in order to dissipate energy as heat. Because of its crucial role in regulating energy homeostasis, ongoing exploration of BAT has emphasized its therapeutic potential in addressing the global epidemics of obesity and diabetes. The recent appreciation that adult humans possess functional BAT strengthens this prospect. Furthermore, it has been identified that there are both classical brown adipocytes residing in dedicated BAT depots and “beige” adipocytes residing in white adipose tissue depots that can acquire BAT-like characteristics in response to environmental cues. This review aims to provide a brief overview of BAT research and summarize recent findings concerning the physiological, cellular, and developmental characteristics of brown adipocytes. In addition, some key genetic, molecular, and pharmacologic targets of BAT/Beige cells that have been reported to have therapeutic potential to combat obesity will be discussed.

Abstract O-2: The Role of Post-translational Modifications in SERCA2a-related Cardiac Dysfunction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Changwon Kho ◽  
Dongtak Jeong ◽  
Ahyoung Lee ◽  
Shinichi Mitsuyama ◽  
Jae Gyun Oh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Critical Role ◽  
Hdac Inhibitors ◽  
Post Translational Modification ◽  
Mice Model ◽  
Down Regulation ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Post Translational Modifications ◽  
Lysine Residues ◽  
Interfering Rna

The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) has become a validated target for the treatment of heart failure (HF). The relationship between reduced SERCA2a activity and decreases in protein expression in the setting of HF has been found to be non-linear and the toxic intracellular milieu in HF contributes to SERCA2a’s dysfunction. Post-translational modification (PTM) of SERCA2a has been recently described to as an important mechanism that can explain a reduction in SERCA2a activity in HF. Based on a comprehensive proteomic analysis, we found that the levels and activity of SERCA2a in cardiomyocytes are modulated in parallel with the levels of small ubiquitin-like modifier type 1 (SUMO-1). Moreover, our work has shown that SUMO-1 plays a critical role in protecting SERCA2a from pathological conditions (Kho et al, Nature, 2011). More recently, we demonstrated that SUMO-1 gene transfer and its combination with SERCA2a led to a reversal of HF in a porcine model of ischemic induced HF (Tilemann et al, Sci Transl Med, 2013). In our analysis of SERCA2a PTM in animal models of HF, we observed that SERCA2a is acetylated, and that this acetylation is more prominent in failing hearts. The acetylation of SERCA2a was validated by acetylation assays with acetyltransferase and HDAC inhibitors. We identified several lysine residues on SERCA2a for susceptible to acetylation. In addition, we found that Sirt1 enzyme deacetylates SERCA2a. Sirt1 down-regulation in HL-1 cells using small interfering RNA increased SERCA2a acetylation and thereby decreased its activity. Moreover, SERCA2a acetylation was increased when Sirt1 was depleted by recombinant adeno-associated virus carrying short hairpin RNA for Sirt1 in mice model, which reflected a decrease in intensity of interaction between Sirt1 and SERCA2a. Reduced acetylation was accompanied by an increase in SERCA2a SUMOylation in the heart. Decreased acetylation, combined with increased SUMOylation, of SERCA2a may contribute to the cardioprotective effects of Sirt1. Our results show that SERCA2a acetylation increases during HF and negatively impacts SERCA2a’s function, suggesting that the down-regulation of SERCA2a acetylation may afford a novel intervention in the setting of heart failure.

Norepinephrine- and insulin-resistant glucose transport in brown adipocytes from diabetic SHR/N-cp rats

1993 ◽  
Vol 265 (3) ◽  
pp. R577-R583
Author(s):  
A. Marette ◽  
P. Mauriege ◽  
J. P. Despres ◽  
O. L. Tulp ◽  
L. J. Bukowiecki
Keyword(s):  
Glucose Metabolism ◽  
Glucose Transport ◽  
Insulin Receptors ◽  
Brown Adipocytes ◽  
Spontaneously Hypertensive ◽  
Insulin Resistant ◽  
Metabolic Defects ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Insulin Responsiveness

The effects of norepinephrine and insulin on glucose transport were investigated in brown adipocytes isolated from obese nondiabetic Lister and Albany (LA/N-cp strain) rats (O-LA), obese diabetic spontaneously hypertensive (SHR/N-cp strain) rats (O-SHR), and from their lean (L) controls to test whether the decreased calorigenic response to norepinephrine of O-SHR adipocytes was specifically associated with alterations in glucose metabolism. Norepinephrine and insulin independently stimulated glucose transport in L-LA, O-LA, and L-SHR brown adipocytes, but their stimulatory effects were markedly reduced in O-SHR cells. Both insulin responsiveness and the total number of insulin receptors were significantly decreased in O-SHR adipocytes but not in O-LA cells. The number of high-affinity beta 1/beta 2-adrenoceptors was significantly increased (+70%) in O-LA adipocytes but was similar in L-SHR and O-SHR cells. These results indicate that 1) major metabolic defects are present in brown adipose tissue (BAT) of O-SHR but not of O-LA, although these two strains are homozygous for the cp allele, 2) postreceptor defects are predominantly involved in O-SHR adipocyte refractoriness to norepinephrine, and 3) a reduced mitochondrial content may represent the principal metabolic alteration explaining the decreased effects of norepinephrine on both thermogenesis and glucose transport. It is postulated that the marked insulin resistance of O-SHR leads to a decreased mitochondriogenesis in BAT, resulting in a diminished tissue thermogenic capacity and reduced glucose metabolism, thereby contributing to obesity and diabetes.

scholarly journals Arsenite exposure suppresses adipogenesis, mitochondrial biogenesis and thermogenesis via autophagy inhibition in brown adipose tissue

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jiyoung Bae ◽  
Yura Jang ◽  
Heejeong Kim ◽  
Kalika Mahato ◽  
Cameron Schaecher ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mitochondrial Biogenesis ◽  
Metabolic Disorders ◽  
High Dose ◽  
Brown Adipocytes ◽  
Treatment And Prevention ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Contaminated Drinking Water

Abstract Arsenite, a trivalent form of arsenic, is an element that occurs naturally in the environment. Humans are exposed to high dose of arsenite through consuming arsenite-contaminated drinking water and food, and the arsenite can accumulate in the human tissues. Arsenite induces oxidative stress, which is linked to metabolic disorders such as obesity and diabetes. Brown adipocytes dissipating energy as heat have emerging roles for obesity treatment and prevention. Therefore, understanding the pathophysiological role of brown adipocytes can provide effective strategies delineating the link between arsenite exposure and metabolic disorders. Our study revealed that arsenite significantly reduced differentiation of murine brown adipocytes and mitochondrial biogenesis and respiration, leading to attenuated thermogenesis via decreasing UCP1 expression. Oral administration of arsenite in mice resulted in heavy accumulation in brown adipose tissue and suppression of lipogenesis, mitochondrial biogenesis and thermogenesis. Mechanistically, arsenite exposure significantly inhibited autophagy necessary for homeostasis of brown adipose tissue through suppression of Sestrin2 and ULK1. These results clearly confirm the emerging mechanisms underlying the implications of arsenite exposure in metabolic disorders.

scholarly journals STALLION: a stacking-based ensemble learning framework for prokaryotic lysine acetylation site prediction

2021 ◽  
Author(s):  
Shaherin Basith ◽  
Gwang Lee ◽  
Balachandran Manavalan
Keyword(s):  
Critical Role ◽  
Lysine Acetylation ◽  
Post Translational Modification ◽  
Disease States ◽  
Regulatory Processes ◽  
Prokaryotic Species ◽  
Lysine Residues ◽  
Predicted Values ◽  
Feature Selection Approach ◽  
Species Specific

Abstract Protein post-translational modification (PTM) is an important regulatory mechanism that plays a key role in both normal and disease states. Acetylation on lysine residues is one of the most potent PTMs owing to its critical role in cellular metabolism and regulatory processes. Identifying protein lysine acetylation (Kace) sites is a challenging task in bioinformatics. To date, several machine learning-based methods for the in silico identification of Kace sites have been developed. Of those, a few are prokaryotic species-specific. Despite their attractive advantages and performances, these methods have certain limitations. Therefore, this study proposes a novel predictor STALLION (STacking-based Predictor for ProkAryotic Lysine AcetyLatION), containing six prokaryotic species-specific models to identify Kace sites accurately. To extract crucial patterns around Kace sites, we employed 11 different encodings representing three different characteristics. Subsequently, a systematic and rigorous feature selection approach was employed to identify the optimal feature set independently for five tree-based ensemble algorithms and built their respective baseline model for each species. Finally, the predicted values from baseline models were utilized and trained with an appropriate classifier using the stacking strategy to develop STALLION. Comparative benchmarking experiments showed that STALLION significantly outperformed existing predictor on independent tests. To expedite direct accessibility to the STALLION models, a user-friendly online predictor was implemented, which is available at: http://thegleelab.org/STALLION.

Review of Progress in Predicting Protein Methylation Sites

2019 ◽  
Vol 23 (15) ◽  
pp. 1663-1670 ◽  
Author(s):  
Chunyan Ao ◽  
Shunshan Jin ◽  
Yuan Lin ◽  
Quan Zou
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Transcriptional Activity ◽  
Regulation Of Gene Expression ◽  
Protein Methylation ◽  
Biological Processes ◽  
Post Translational Modification ◽  
Regulatory Enzymes ◽  
Lysine Residues ◽  
Arginine Residues

Protein methylation is an important and reversible post-translational modification that regulates many biological processes in cells. It occurs mainly on lysine and arginine residues and involves many important biological processes, including transcriptional activity, signal transduction, and the regulation of gene expression. Protein methylation and its regulatory enzymes are related to a variety of human diseases, so improved identification of methylation sites is useful for designing drugs for a variety of related diseases. In this review, we systematically summarize and analyze the tools used for the prediction of protein methylation sites on arginine and lysine residues over the last decade.

Pathogenesis of Age-related Cataract: a systematic review of proteomic studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Christina Karakosta ◽  
Argyrios Tzamalis ◽  
Michalis Aivaliotis ◽  
Ioannis Tsinopoulos
Keyword(s):  
Systematic Review ◽  
Oxidant Stress ◽  
Critical Role ◽  
Human Lens ◽  
Nuclear Cataract ◽  
Cataract Formation ◽  
Post Translational Modification ◽  
Ability To Act ◽  
Age Related

Background/Objective:: The aim of this systematic review is to identify all the available data on human lens proteomics with a critical role to age-related cataract formation in order to elucidate the physiopathology of the aging lens. Materials and Methods:: We searched on Medline and Cochrane databases. The search generated 328 manuscripts. We included nine original proteomic studies that investigated human cataractous lenses. Results:: Deamidation was the major age-related post-translational modification. There was a significant increase in the amount of αA-crystallin D-isoAsp58 present at all ages, while an increase in the extent of Trp oxidation was apparent in cataract lenses when compared to aged normal lenses. During aging, enzymes with oxidized cysteine at critical sites included GAPDH, glutathione synthase, aldehyde dehydrogenase, sorbitol dehydrogenase, and PARK7. Conclusion:: D-isoAsp in αA crystallin could be associated with the development of age-related cataract in human, by contributing to the denaturation of a crystallin, and decreasing its ability to act as a chaperone. Oxidation of Trp may be associated with nuclear cataract formation in human, while the role of oxidant stress in age-related cataract formation is dominant.

Sign in / Sign up

Export Citation Format

Share Document