scholarly journals Fine-tuning autophagy: from transcriptional to posttranslational regulation

2016 ◽  
Vol 311 (3) ◽  
pp. C351-C362 ◽  
Author(s):  
Joëlle Botti-Millet ◽  
Anna Chiara Nascimbeni ◽  
Nicolas Dupont ◽  
Etienne Morel ◽  
Patrice Codogno
Keyword(s):  
Posttranslational Modifications ◽  
Inflammatory Responses ◽  
Chronic Inflammatory Disease ◽  
Autophagic Vacuole ◽  
Tissue Homeostasis ◽  
Fine Tuning ◽  
Eukaryotic Cells ◽  
Posttranslational Regulation ◽  
Atg Proteins ◽  
Diabetes And Obesity

Macroautophagy (hereafter called autophagy) is a vacuolar lysosomal pathway for degradation of intracellular material in eukaryotic cells. Autophagy plays crucial roles in tissue homeostasis, in adaptation to stress situations, and in immune and inflammatory responses. Alteration of autophagy is associated with cancer, diabetes and obesity, cardiovascular disease, neurodegenerative disease, autoimmune disease, infection, and chronic inflammatory disease. Autophagy is controlled by autophagy-related (ATG) proteins that act in a coordinated manner to build up the initial autophagic vacuole named the autophagosome. It is now known that the activities of ATG proteins are modulated by posttranslational modifications such as phosphorylation, ubiquitination, and acetylation. Moreover, transcriptional and epigenetic controls are involved in the regulation of autophagy in stress situations. Here we summarize and discuss how posttranslational modifications and transcriptional and epigenetic controls regulate the involvement of autophagy in the proteostasis network.

scholarly journals Deficiency of Lipin2 Results in Enhanced NF-κB Signaling and Osteoclast Formation in RAW-D Murine Macrophages

2021 ◽  
Vol 22 (6) ◽  
pp. 2893
Author(s):  
Asami Watahiki ◽  
Seira Hoshikawa ◽  
Mitsuki Chiba ◽  
Hiroshi Egusa ◽  
Satoshi Fukumoto ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Osteoclast Formation ◽  
Fine Tuning ◽  
Nuclear Accumulation ◽  
Innate Immune Responses ◽  
Osteoclastic Resorption ◽  
Bone Disorder ◽  
Proinflammatory Responses ◽  
Potential Therapeutic Intervention

Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in Lpin2, which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a Lpin2 knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.

scholarly journals Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3446
Author(s):  
Stefan Koch
Keyword(s):  
Transcription Factors ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Treatment Options ◽  
Wnt Signaling Pathway ◽  
Tissue Homeostasis ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Forkhead Box ◽  
Signaling Activity

Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.

scholarly journals Examining and Fine-tuning the Selection of Glycan Compositions with GlyConnect Compozitor

2020 ◽  
Vol 19 (10) ◽  
pp. 1602-1618 ◽  
Author(s):  
Thibault Robin ◽  
Julien Mariethoz ◽  
Frédérique Lisacek
Keyword(s):  
Search Engine ◽  
Posttranslational Modifications ◽  
Search Engines ◽  
Web Application ◽  
Contextual Information ◽  
Fine Tuning ◽  
Data Sources ◽  
Web Interface ◽  
Definition Of ◽  
Selection Of

A key point in achieving accurate intact glycopeptide identification is the definition of the glycan composition file that is used to match experimental with theoretical masses by a glycoproteomics search engine. At present, these files are mainly built from searching the literature and/or querying data sources focused on posttranslational modifications. Most glycoproteomics search engines include a default composition file that is readily used when processing MS data. We introduce here a glycan composition visualizing and comparative tool associated with the GlyConnect database and called GlyConnect Compozitor. It offers a web interface through which the database can be queried to bring out contextual information relative to a set of glycan compositions. The tool takes advantage of compositions being related to one another through shared monosaccharide counts and outputs interactive graphs summarizing information searched in the database. These results provide a guide for selecting or deselecting compositions in a file in order to reflect the context of a study as closely as possible. They also confirm the consistency of a set of compositions based on the content of the GlyConnect database. As part of the tool collection of the Glycomics@ExPASy initiative, Compozitor is hosted at https://glyconnect.expasy.org/compozitor/ where it can be run as a web application. It is also directly accessible from the GlyConnect database.

scholarly journals Minireview: Epigenetic Programming of Diabetes and Obesity: Animal Models

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1031-1038 ◽  
Author(s):  
Yoshinori Seki ◽  
Lyda Williams ◽  
Patricia M. Vuguin ◽  
Maureen J. Charron
Keyword(s):  
Metabolic Disease ◽  
Animal Models ◽  
Posttranslational Modifications ◽  
Cytosine Methylation ◽  
Metabolic Diseases ◽  
Later Life ◽  
Epigenetic Modifications ◽  
Micro Rna ◽  
Fetal Origins ◽  
Diabetes And Obesity

A growing body of evidence suggests that the intrauterine (IU) environment has a significant and lasting effect on the long-term health of the growing fetus and the development of metabolic disease in later life as put forth in the fetal origins of disease hypothesis. Metabolic diseases have been associated with alterations in the epigenome that occur without changes in the DNA sequence, such as cytosine methylation of DNA, histone posttranslational modifications, and micro-RNA. Animal models of epigenetic modifications secondary to an altered IU milieu are an invaluable tool to study the mechanisms that determine the development of metabolic diseases, such as diabetes and obesity. Rodent and nonlitter bearing animals are good models for the study of disease, because they have similar embryology, anatomy, and physiology to humans. Thus, it is feasible to monitor and modify the IU environment of animal models in order to gain insight into the molecular basis of human metabolic disease pathogenesis. In this review, the database of PubMed was searched for articles published between 1999 and 2011. Key words included epigenetic modifications, IU growth retardation, small for gestational age, animal models, metabolic disease, and obesity. The inclusion criteria used to select studies included animal models of epigenetic modifications during fetal and neonatal development associated with adult metabolic syndrome. Experimental manipulations included: changes in the nutritional status of the pregnant female (calorie-restricted, high-fat, or low-protein diets during pregnancy), as well as the father; interference with placenta function, or uterine blood flow, environmental toxin exposure during pregnancy, as well as dietary modifications during the neonatal (lactation) as well as pubertal period. This review article is focused solely on studies in animal models that demonstrate epigenetic changes that are correlated with manifestation of metabolic disease, including diabetes and/or obesity.

Abstract 249: Increased Vascular CCRL2 Expression by Disturbed Blood Flow Promotes Atherosclerotic Plaque Formation in ApoE Deficient Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Shuhong Hu ◽  
Li Zhu
Keyword(s):  
Blood Flow ◽  
Atherosclerotic Plaque ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Vascular Wall ◽  
Chronic Inflammatory Disease ◽  
Plaque Formation ◽  
Foam Cell Formation ◽  
Cell Trafficking

Atherosclerosis is a chronic inflammatory disease of the arterial wall elicited by accumulation of LDL and leucocytes in the subendothelium at predilection sites with disturbed laminar flow. Chemokines and their receptors appear to act as critical players in atherosclerosis as they not only direct atherogenic recruitment of leucocytes but also exert cell hemostatic functions by chemokine ligand-receptor axes and their specific or combined contributions. Atypical chemokine (C-C motif) receptor-like 2 (CCRL2) cooperates with its ligand chemerin and leukocyte-expressed chemerin receptor chemokine-like receptor 1 (CMKLR1) to regulate cell trafficking and inflammatory responses,but its role in atherosclerosis is not clear. To investigate whether CCRL2 contributes to the pathomechanism of atherogenesis, we generated CCRL2 -/- mice in hyperlipidemic atherosclerosis-prone ApoE -/- background and found that the atherosclerotic plaque area of the total aorta was significantly reduced compared with CCRL2 +/+ ApoE -/- mice on a high fat diet. The protective effect of CCRL2 deficiency was anatomically isolated primarily to the site of disturbed blood flow (D-flow) in the aortic arch but not in the descending aorta. Endothelial CCRL2 was upregulated in response to D-flow and either CCRL2 or CMKLR1 deletion reduced plaque formation. Further studies showed that CCRL2 co-localized with CMKLR1 and chemerin within the atherosclerotic aorta root. CCRL2 deficiency led to significantly less lipid deposition in aortic root, reduced CMKLR1 + leukocyte rolling on lesional vascular endothelium, diminished macrophage accumulation and foam cell formation, and polarized macrophage to an M2-like phenotype. These results demonstrate that D-flow induction of vascular CCRL2 is required for optimal formation of atherosclerotic plaques via coordinating the accumulation of CMKLR1 + monocytes/macrophages within the vascular wall, and thus identifies CCRL2 as a novel drug target to prevent or treat atherosclerosis. This work was supported by Natural Science Foundation of China (grant 81370373 to L.Z. and 31300781 to C.T.) Key Words: atherosclerosis, CCRL2, chemerin, macrophage

scholarly journals Posttranslational modifications control FoxO3 activity during denervation

2012 ◽  
Vol 302 (3) ◽  
pp. C587-C596 ◽  
Author(s):  
Enrico Bertaggia ◽  
Luisa Coletto ◽  
Marco Sandri
Keyword(s):  
Posttranslational Modifications ◽  
Critical Role ◽  
Fine Tuning ◽  
Histone Acetyl Transferase ◽  
Forkhead Box ◽  
Lysine Residues ◽  
Ubiquitin Proteasome ◽  
Fine Regulation ◽  
Bona Fide ◽  
Rate Limiting

Loss of muscle mass occurs in a variety of diseases including cancer, chronic heart failure, AIDS, diabetes, and renal failure, often aggravating pathological progression. The atrophy process is controlled by a transcriptional program that regulates the expression of a subset of genes named atrophy-related genes. The Forkhead Box O (FoxO) family of transcription factors plays a critical role in the atrophy program being sufficient and necessary for the expression of rate-limiting enzymes of ubiquitin-proteasome and autophagy-lysosome systems. Therefore, a fine regulation of FoxOs is critical to avoid excessive proteolysis and cachexia. FoxO activity can be modulated by different mechanisms including phosphorylation, acetylation, ubiquitination, and glycosylation. Here we show that FoxO3 is progressively acetylated during denervation and concomitantly atrogin-1, the bona fide FoxO3 target, is downregulated. FoxO3 interacts with the histone acetyl-transferase p300, and its acetylation causes cytosolic relocalization and degradation. Several lysine residues of FoxOs are known to be acetylated. To identify which lysines are critical for FoxO3 activity we have generated different FoxO3 mutants that either mimic or prevent lysine acetylation. We found that FoxO3 mutants that mimic acetylation show a decrease of transcriptional activity and cytosolic localization. Importantly, acetylation induces FoxO3 degradation via proteasome system. Between the different lysines, lysine 262 is critical for translocation of FoxO3. In conclusion, we provide evidence that FoxO3 activity is negatively modulated by acetylation and ubiquitination in a time-dependent and coordinated manner. This fine-tuning mechanism of FoxO3 regulation may be important to prevent excessive muscle loss and can be used as a therapeutic approach to counteract muscle wasting.

scholarly journals The Arg/N-Degron Pathway—A Potential Running Back in Fine-Tuning the Inflammatory Response?

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 903
Author(s):  
Dominique Leboeuf ◽  
Maxim Pyatkov ◽  
Timofei S. Zatsepin ◽  
Konstantin Piatkov
Keyword(s):  
Inflammatory Responses ◽  
Fine Tuning ◽  
Protein Fragments ◽  
E3 Ligases ◽  
Selective Degradation ◽  
Proinflammatory Mediators ◽  
Proteolytic Pathway ◽  
Inflammatory Processes ◽  
A Cell ◽  
Inflammatory Caspases

Recognition of danger signals by a cell initiates a powerful cascade of events generally leading to inflammation. Inflammatory caspases and several other proteases become activated and subsequently cleave their target proinflammatory mediators. The irreversible nature of this process implies that the newly generated proinflammatory fragments need to be sequestered, inhibited, or degraded in order to cancel the proinflammatory program or prevent chronic inflammation. The Arg/N-degron pathway is a ubiquitin-dependent proteolytic pathway that specifically degrades protein fragments bearing N-degrons, or destabilizing residues, which are recognized by the E3 ligases of the pathway. Here, we report that the Arg/N-degron pathway selectively degrades a number of proinflammatory fragments, including some activated inflammatory caspases, contributing in tuning inflammatory processes. Partial ablation of the Arg/N-degron pathway greatly increases IL-1β secretion, indicating the importance of this ubiquitous pathway in the initiation and resolution of inflammation. Thus, we propose a model wherein the Arg/N-degron pathway participates in the control of inflammation in two ways: in the generation of inflammatory signals by the degradation of inhibitory anti-inflammatory domains and as an “off switch” for inflammatory responses through the selective degradation of proinflammatory fragments.

scholarly journals Fine Tuning Cell Migration by a Disintegrin and Metalloproteinases

2017 ◽  
Vol 2017 ◽  
pp. 1-22 ◽  
Author(s):  
D. Dreymueller ◽  
K. Theodorou ◽  
M. Donners ◽  
A. Ludwig
Keyword(s):  
Cell Migration ◽  
Cell Polarity ◽  
Immune Cell ◽  
Tissue Homeostasis ◽  
Fine Tuning ◽  
Tissue Cell ◽  
Cancer Cell Migration ◽  
Physiological Processes ◽  
Cell Tissue ◽  
And Migration

Cell migration is an instrumental process involved in organ development, tissue homeostasis, and various physiological processes and also in numerous pathologies. Both basic cell migration and migration towards chemotactic stimulus consist of changes in cell polarity and cytoskeletal rearrangement, cell detachment from, invasion through, and reattachment to their neighboring cells, and numerous interactions with the extracellular matrix. The different steps of immune cell, tissue cell, or cancer cell migration are tightly coordinated in time and place by growth factors, cytokines/chemokines, adhesion molecules, and receptors for these ligands. This review describes how a disintegrin and metalloproteinases interfere with several steps of cell migration, either by proteolytic cleavage of such molecules or by functions independent of proteolytic activity.

scholarly journals Glucose regulates clathrin adaptors at the trans-Golgi network and endosomes

2011 ◽  
Vol 22 (19) ◽  
pp. 3671-3683 ◽  
Author(s):  
Quyen L. Aoh ◽  
Lee M. Graves ◽  
Mara C. Duncan
Keyword(s):  
Cell Polarity ◽  
Translation Initiation ◽  
Posttranslational Modifications ◽  
Raw Material ◽  
Eukaryotic Cells ◽  
Glucose Starvation ◽  
Yeast Saccharomyces Cerevisiae ◽  
Trans Golgi Network ◽  
Golgi Network ◽  
Biomass Increase

Glucose is a rich source of energy and the raw material for biomass increase. Many eukaryotic cells remodel their physiology in the presence and absence of glucose. The yeast Saccharomyces cerevisiae undergoes changes in transcription, translation, metabolism, and cell polarity in response to glucose availability. Upon glucose starvation, translation initiation and cell polarity are immediately inhibited, and then gradually recover. In this paper, we provide evidence that, as in cell polarity and translation, traffic at the trans-Golgi network (TGN) and endosomes is regulated by glucose via an unknown mechanism that depends on protein kinase A (PKA). Upon glucose withdrawal, clathrin adaptors exhibit a biphasic change in localization: they initially delocalize from the membrane within minutes and later partially recover onto membranes. Additionally, the removal of glucose induces changes in posttranslational modifications of adaptors. Ras and Gpr1 signaling pathways, which converge on PKA, are required for changes in adaptor localization and changes in posttranslational modifications. Acute inhibition of PKA demonstrates that inhibition of PKA prior to glucose withdrawal prevents several adaptor responses to starvation. This study demonstrates that PKA activity prior to glucose starvation primes membrane traffic at the TGN and endosomes in response to glucose starvation.

Cellular immunity, low-density lipoprotein and atherosclerosis: Break of tolerance in the artery wall

2011 ◽  
Vol 106 (11) ◽  
pp. 779-786 ◽  
Author(s):  
Daniel Ketelhuth ◽  
Göran Hansson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cellular Immunity ◽  
Inflammatory Responses ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Chronic Inflammatory Disease ◽  
Research Field ◽  
T Cell Subsets ◽  
Low Density

SummaryAtherosclerosis is a chronic inflammatory disease. Atherosclerotic plaques contain abundant immune cells that can dictate and effect inflammatory responses. Among them, T cells are present during all stages of the disease suggesting that they are essential in the initiation as well as the progression of plaque. Experimental as well as clinical research has demonstrated different T cell subsets, i.e. CD4+ Th1, Th2, Th17, and Treg as well as CD8+ and NKT cells in the plaque. Moreover, candidate antigens inducing T cell responses have been identified. Knowledge about the pathological role of these cells in atherogenesis may lead to development of new therapies. This review provides an overview of the research field of cellular immunity in atherosclerosis. It emphasises the events and findings involving antigen specific T cells, in particular low-density lipoprotein-specific T cells.

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