Posttranslational modifications control FoxO3 activity during denervation

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.

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Adiponectin Multimerization Is Dependent on Conserved Lysines in the Collagenous Domain: Evidence for Regulation of Multimerization by Alterations in Posttranslational Modifications

Molecular Endocrinology ◽

10.1210/me.2005-0390 ◽

2006 ◽

Vol 20 (7) ◽

pp. 1673-1687 ◽

Cited By ~ 121

Author(s):

Ayanthi A. Richards ◽

Tim Stephens ◽

Hayley K. Charlton ◽

Alun Jones ◽

Graeme A. Macdonald ◽

...

Keyword(s):

Posttranslational Modifications ◽

Disulfide Bonds ◽

Molecular Mechanisms ◽

Physiological Factors ◽

Mammalian Cell Lines ◽

Lysine Residues ◽

Bona Fide ◽

Multimeric Protein ◽

Collagenous Domain

Abstract Adiponectin is a secreted, multimeric protein with insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Serum adiponectin consists of trimer, hexamer, and larger high-molecular-weight (HMW) multimers, and these HMW multimers appear to be the more bioactive forms. Multimer composition of adiponectin appears to be regulated; however, the molecular mechanisms involved are unknown. We hypothesize that regulation of adiponectin multimerization and secretion occurs via changes in posttranslational modifications (PTMs). Although a structural role for intertrimer disulfide bonds in the formation of hexamers and HMW multimers is established, the role of other PTMs is unknown. PTMs identified in murine and bovine adiponectin include hydroxylation of multiple conserved proline and lysine residues and glycosylation of hydroxylysines. By mass spectrometry, we confirmed the presence of these PTMs in human adiponectin and identified three additional hydroxylations on Pro71, Pro76, and Pro95. We also investigated the role of the five modified lysines in multimer formation and secretion of recombinant human adiponectin expressed in mammalian cell lines. Mutation of modified lysines in the collagenous domain prevented formation of HMW multimers, whereas a pharmacological inhibitor of prolyl- and lysyl-hydroxylases, 2,2′-dipyridyl, inhibited formation of hexamers and HMW multimers. Bacterially expressed human adiponectin displayed a complete lack of differentially modified isoforms and failed to form bona fide trimers and larger multimers. Finally, glucose-induced increases in HMW multimer production from human adipose explants correlated with changes in the two-dimensional electrophoresis profile of adiponectin isoforms. Collectively, these data suggest that adiponectin multimer composition is affected by changes in PTM in response to physiological factors.

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Regulation of p53 by E3s

Cancers ◽

10.3390/cancers13040745 ◽

2021 ◽

Vol 13 (4) ◽

pp. 745

Author(s):

Mengwu Pan ◽

Christine Blattner

Keyword(s):

Posttranslational Modifications ◽

Target Genes ◽

Cell Cycle Control ◽

Normal Growth ◽

Ubiquitin Proteasome System ◽

Growth Conditions ◽

Ubiquitin Proteasome ◽

Bona Fide ◽

Cell Expression ◽

Species Production

More than 40 years of research on p53 have given us tremendous knowledge about this protein. Today we know that p53 plays a role in different biological processes such as proliferation, invasion, pluripotency, metabolism, cell cycle control, ROS (reactive oxygen species) production, apoptosis, inflammation and autophagy. In the nucleus, p53 functions as a bona-fide transcription factor which activates and represses transcription of a number of target genes. In the cytoplasm, p53 can interact with proteins of the apoptotic machinery and by this also induces cell death. Despite being so important for the fate of the cell, expression levels of p53 are kept low in unstressed cells and the protein is largely inactive. The reason for the low expression level is that p53 is efficiently degraded by the ubiquitin-proteasome system and the vast inactivity of the tumor suppressor protein under normal growth conditions is due to the absence of activating and the presence of inactivating posttranslational modifications. E3s are important enzymes for these processes as they decorate p53 with ubiquitin and small ubiquitin-like proteins and by this control p53 degradation, stability and its subcellular localization. In this review, we provide an overview about E3s that target p53 and discuss the connection between p53, E3s and tumorigenesis.

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Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems

International Journal of Molecular Sciences ◽

10.3390/ijms22031031 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1031

Author(s):

Naoko Niimi ◽

Hideji Yako ◽

Shizuka Takaku ◽

Sookja K. Chung ◽

Kazunori Sango

Keyword(s):

Schwann Cells ◽

Aldose Reductase ◽

Critical Role ◽

Polyol Pathway ◽

Glucose Flux ◽

Rate Limiting ◽

Deficient Mice ◽

Excess Glucose ◽

Shed Light ◽

Immortalized Schwann Cells

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

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Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Cancers ◽

10.3390/cancers13143446 ◽

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.

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

Molecular & Cellular Proteomics ◽

10.1074/mcp.ra120.002041 ◽

2020 ◽

Vol 19 (10) ◽

pp. 1602-1618 ◽

Cited By ~ 1

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.

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Fine-tuning autophagy: from transcriptional to posttranslational regulation

AJP Cell Physiology ◽

10.1152/ajpcell.00129.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. C351-C362 ◽

Cited By ~ 17

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.

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Molecular mechanisms of mammalian autophagy

Biochemical Journal ◽

10.1042/bcj20210314 ◽

2021 ◽

Vol 478 (18) ◽

pp. 3395-3421

Author(s):

Charles B. Trelford ◽

Gianni M. Di Guglielmo

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Molecular Pathways ◽

Zymogen Granules ◽

Ubiquitin Proteasome Pathway ◽

Lysine Residues ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Functional Modulation ◽

Chaperone Mediated Autophagy

The ubiquitin-proteasome pathway (UPP) and autophagy play integral roles in cellular homeostasis. As part of their normal life cycle, most proteins undergo ubiquitination for some form of redistribution, localization and/or functional modulation. However, ubiquitination is also important to the UPP and several autophagic processes. The UPP is initiated after specific lysine residues of short-lived, damaged or misfolded proteins are conjugated to ubiquitin, which targets these proteins to proteasomes. Autophagy is the endosomal/lysosomal-dependent degradation of organelles, invading microbes, zymogen granules and macromolecules such as protein, carbohydrates and lipids. Autophagy can be broadly separated into three distinct subtypes termed microautophagy, chaperone-mediated autophagy and macroautophagy. Although autophagy was once thought of as non-selective bulk degradation, advancements in the field have led to the discovery of several selective forms of autophagy. Here, we focus on the mechanisms of primary and selective mammalian autophagy pathways and highlight the current knowledge gaps in these molecular pathways.

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Fine-tuning the ubiquitin-proteasome system to treat pulmonary fibrosis

Connective Tissue Research ◽

10.1080/03008207.2018.1529174 ◽

2018 ◽

Vol 60 (1) ◽

pp. 50-61 ◽

Cited By ~ 3

Author(s):

Willy Roque ◽

Ross Summer ◽

Freddy Romero

Keyword(s):

Pulmonary Fibrosis ◽

Ubiquitin Proteasome System ◽

Fine Tuning ◽

Ubiquitin Proteasome

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Neuron-class specific responses govern adaptive remodeling of myelination in the neocortex

10.1101/2020.08.23.263681 ◽

2020 ◽

Author(s):

Sung Min Yang ◽

Katrin Michel ◽

Vahbiz Jokhi ◽

Elly Nedivi ◽

Paola Arlotta

Keyword(s):

Critical Role ◽

Sensory Experience ◽

Monocular Deprivation ◽

Fine Tuning ◽

Initial Increase ◽

Projection Neurons ◽

Myelin Sheaths ◽

Adaptive Circuit ◽

Callosal Projection

AbstractMyelination plasticity plays a critical role in neurological function, including learning and memory. However, it is unknown whether this plasticity is enacted through uniform changes across all neuronal subtypes, or whether myelin dynamics vary between neuronal classes to enable fine-tuning of adaptive circuit responses. We performed in vivo two-photon imaging to investigate the dynamics of myelin sheaths along single axons of both excitatory callosal projection neurons and inhibitory parvalbumin+ interneurons in layer 2/3 of adult mouse visual cortex. We find that both neuron types show dynamic, homeostatic myelin remodeling under normal vision. However, monocular deprivation results in experience-dependent adaptive myelin remodeling only in parvalbumin+ interneurons, but not in callosal projection neurons. Monocular deprivation induces an initial increase in elongation events in myelin segments of parvalbumin+ interneurons, followed by a contraction phase affecting a separate cohort of segments. Sensory experience does not alter the generation rate of new myelinating oligodendrocytes, but can recruit pre-existing oligodendrocytes to generate new myelin sheaths. Parvalbumin+ interneurons also show a concomitant increase in axonal branch tip dynamics independent from myelination events. These findings suggest that adaptive myelination is part of a coordinated suite of circuit reconfiguration processes, and demonstrate that distinct classes of neocortical neurons individualize adaptive remodeling of their myelination profiles to diversify circuit tuning in response to sensory experience.

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