scholarly journals Regulation of Glucose Metabolism by NAD+ and ADP-Ribosylation

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 890 ◽  
Author(s):  
Hopp ◽  
Grüter ◽  
Hottiger
Keyword(s):  
Glucose Metabolism ◽  
Metabolic Pathways ◽  
Redox Reactions ◽  
Genotoxic Stress ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Cellular Processes ◽  
Energy Needs ◽  
Cellular Compartments

Cells constantly adapt their metabolic pathways to meet their energy needs and respond to nutrient availability. During the last two decades, it has become increasingly clear that NAD+, a coenzyme in redox reactions, also mediates several ubiquitous cell signaling processes. Protein ADP-ribosylation is a post-translational modification that uses NAD+ as a substrate and is best known as part of the genotoxic stress response. However, there is increasing evidence that NAD+-dependent ADP-ribosylation regulates other cellular processes, including metabolic pathways. In this review, we will describe the compartmentalized regulation of NAD+ biosynthesis, consumption, and regeneration with a particular focus on the role of ADP-ribosylation in the regulation of glucose metabolism in different cellular compartments.

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.

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.

ADP-ribosylation and intracellular traffic: an emerging role for PARP enzymes

2019 ◽  
Vol 47 (1) ◽  
pp. 357-370 ◽  
Author(s):  
Giovanna Grimaldi ◽  
Daniela Corda
Keyword(s):  
Intracellular Transport ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Intracellular Traffic ◽  
Adp Ribosylation ◽  
Cell Responses ◽  
Physiological Processes ◽  
Dependent Cell ◽  
Ribose Moiety

AbstractADP-ribosylation is an ancient and reversible post-translational modification (PTM) of proteins, in which the ADP-ribose moiety is transferred from NAD+ to target proteins by members of poly-ADP-ribosyl polymerase (PARP) family. The 17 members of this family have been involved in a variety of cellular functions, where their regulatory roles are exerted through the modification of specific substrates, whose identification is crucial to fully define the contribution of this PTM. Evidence of the role of the PARPs is now available both in the context of physiological processes and of cell responses to stress or starvation. An emerging role of the PARPs is their control of intracellular transport, as it is the case for tankyrases/PARP5 and PARP12. Here, we discuss the evidence pointing at this novel aspect of PARPs-dependent cell regulation.

Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease

2011 ◽  
Vol 439 (3) ◽  
pp. 349-378 ◽  
Author(s):  
Anthony J. Morgan ◽  
Frances M. Platt ◽  
Emyr Lloyd-Evans ◽  
Antony Galione
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Processes ◽  
Late Endosomes ◽  
Wide Range ◽  
Health And Disease ◽  
Lysosome Related Organelles ◽  
Cellular Compartments ◽  
Endosomal Vesicles ◽  
Intracellular Targets

Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.

scholarly journals In vivo vizualisation of mono-ADP-ribosylation by dPARP16 upon amino-acid starvation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Angelica Aguilera-Gomez ◽  
Marinke M van Oorschot ◽  
Tineke Veenendaal ◽  
Catherine Rabouille
Keyword(s):  
Amino Acid ◽  
Metabolic Stress ◽  
Amino Acid Starvation ◽  
Critical Event ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Body Component ◽  
Necessary And Sufficient

PARP catalysed ADP-ribosylation is a post-translational modification involved in several physiological and pathological processes, including cellular stress. In order to visualise both Poly-, and Mono-, ADP-ribosylation in vivo, we engineered specific fluorescent probes. Using them, we show that amino-acid starvation triggers an unprecedented display of mono-ADP-ribosylation that governs the formation of Sec body, a recently identified stress assembly that forms in Drosophila cells. We show that dPARP16 catalytic activity is necessary and sufficient for both amino-acid starvation induced mono-ADP-ribosylation and subsequent Sec body formation and cell survival. Importantly, dPARP16 catalyses the modification of Sec16, a key Sec body component, and we show that it is a critical event for the formation of this stress assembly. Taken together our findings establish a novel example for the role of mono-ADP-ribosylation in the formation of stress assemblies, and link this modification to a metabolic stress.

scholarly journals When the chains do not break: the role of USP10 in physiology and pathology

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Udayan Bhattacharya ◽  
Fiifi Neizer-Ashun ◽  
Priyabrata Mukherjee ◽  
Resham Bhattacharya
Keyword(s):  
Complex Formation ◽  
Molecular Mechanisms ◽  
Protein Homeostasis ◽  
Post Translational Modification ◽  
Intracellular Protein ◽  
Lysosomal Degradation ◽  
Life Activity ◽  
Cellular Processes ◽  
Pathological Conditions

AbstractDeubiquitination is now understood to be as important as its partner ubiquitination for the maintenance of protein half-life, activity, and localization under both normal and pathological conditions. The enzymes that remove ubiquitin from target proteins are called deubiquitinases (DUBs) and they regulate a plethora of cellular processes. DUBs are essential enzymes that maintain intracellular protein homeostasis by recycling ubiquitin. Ubiquitination is a post-translational modification where ubiquitin molecules are added to proteins thus influencing activation, localization, and complex formation. Ubiquitin also acts as a tag for protein degradation, especially by proteasomal or lysosomal degradation systems. With ~100 members, DUBs are a large enzyme family; the ubiquitin-specific peptidases (USPs) being the largest group. USP10, an important member of this family, has enormous significance in diverse cellular processes and many human diseases. In this review, we discuss recent studies that define the roles of USP10 in maintaining cellular function, its involvement in human pathologies, and the molecular mechanisms underlying its association with cancer and neurodegenerative diseases. We also discuss efforts to modulate USPs as therapy in these diseases.

scholarly journals Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 680
Author(s):  
Ann-Katrin Hopp ◽  
Michael O. Hottiger
Keyword(s):  
Nucleic Acids ◽  
Nicotinamide Adenine Dinucleotide ◽  
Physiological Function ◽  
Adenosine Diphosphate ◽  
Current Understanding ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Cellular Processes ◽  
The Past ◽  
Technological Advances

Adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD+)-dependent post-translational modification that is found on proteins as well as on nucleic acids. While ARTD1/PARP1-mediated poly-ADP-ribosylation has extensively been studied in the past 60 years, comparably little is known about the physiological function of mono-ADP-ribosylation and the enzymes involved in its turnover. Promising technological advances have enabled the development of innovative tools to detect NAD+ and NAD+/NADH (H for hydrogen) ratios as well as ADP-ribosylation. These tools have significantly enhanced our current understanding of how intracellular NAD dynamics contribute to the regulation of ADP-ribosylation as well as to how mono-ADP-ribosylation integrates into various cellular processes. Here, we discuss the recent technological advances, as well as associated new biological findings and concepts.

scholarly journals Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021 ◽  
Vol 14 (9) ◽  
pp. 848
Author(s):  
Lucas Cruz ◽  
Paula Soares ◽  
Marcelo Correia
Keyword(s):  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
Ubiquitin Molecule

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

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 ADP-ribosylation of mitochondrial proteins is mediated by Neuralized-like protein 4 (NEURL4)

2020 ◽  
Author(s):  
Maria Dafne Cardamone ◽  
Yuan Gao ◽  
Julian Kwan ◽  
Vanessa Hayashi ◽  
Megan Sheeran ◽  
...  
Keyword(s):  
Excision Repair ◽  
Mitochondrial Proteins ◽  
Exact Nature ◽  
Post Translational Modification ◽  
Adp Ribosylation ◽  
Regulatory Strategy ◽  
Mitochondrial Functions ◽  
Specific Proteins ◽  
Base Excision ◽  
Cellular Compartments

ADP-ribosylation is a reversible post-translational modification where an ADP-ribose moiety is covalently attached to amino acid side-chains of target proteins either as mono-ADP-ribose (MARylation or MAR) or poly-ADP-ribose chains (PARylation or PAR) by a class of enzymes called ADP-ribosyltransferases (ARTs). Although ADP-ribosylation is best known for its nuclear roles, ADP-ribosylation of extra nuclear proteins is increasingly recognized as a key regulatory strategy across cellular compartments. ADP-ribosylation of mitochondrial proteins, in particular, has been widely reported, even though the extent to which ADP-ribosylation of specific proteins regulates mitochondrial functions is unclear and the exact nature of mitochondrial ART enzymes is debated.Here, we have identified Neuralized-like protein 4 (NEURL4) as a mitochondrial ART enzyme and profiled the NEURL4-dependent ADP-ribosylome in mitochondrial extracts from Hela cells by LC-MS/MS, using isobaric tandem mass tag (TMT) labeling for relative quantification. Comparison of WT and NEURL4-KO cells generated by CRISPR/Cas9 genome editing revealed that most ART activity associated with mitochondria is lost in absence of NEURL4. Putative NEURL4 targets include numerous mitochondrial proteins previously shown to be ADP-ribosylated. In particular, we show that NEURL4 enzymatic activity is required for the regulation of mtDNA integrity via poly-ADP-ribosylation of mitochondrial specific Ligase III (mtLIG3), the rate-limiting enzyme for mitochondrial DNA (mtDNA) Base Excision Repair (BER).Collectively, our studies reveal that NEURL4 acts as the main mitochondrial ART enzyme under physiological conditions and provide novel insights in the regulation of mitochondria homeostasis through ADP-ribosylation.

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