Abstract MP218: Cop9 Signalosome Subunit 6 Restricts Desmosomal Proteome Degradation To Prevent Desmosomal Targeted Cardiac Disease

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Yan Liang ◽  
Robert Lyon ◽  
Jason Pellman ◽  
William Bradford ◽  
Stephan Lange ◽  
...  
Keyword(s):  
Mouse Models ◽  
Cardiac Disease ◽  
Cell Communication ◽  
Cop9 Signalosome ◽  
Tissue Architecture ◽  
Protein Loss ◽  
Enzymatic Function ◽  
Regulatory Complex ◽  
And Function ◽  
Desmosomal Protein

Dysregulated protein degradative pathways are increasingly recognized as mediators of human cardiac disease. This pathway may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication. Genetic mutations in desmosomal genes resulting in the destabilization/breakdown of the desmosomal proteome are a central hallmark of all genetic-based desmosomal-targeted diseases, including the cardiac disease arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here we identified a desmosomal resident regulatory complex, composed of subunit 6 of the COP9 signalosome (CSN6), enzymatically restricted neddylation and targets desmosomal proteome. Pharmacological restoration of CSN enzymatic function (via neddylation inhibitors) could rescue desmosomal protein loss in CSN6 deficient cardiomyocytes. Through the generation of two novel mouse models, we showed that cardiomyocyte-restricted CSN6 loss in mice selectively accelerated desmosomal destruction to trigger classic disease features associated with ARVD/C. We further showed that disruption of CSN6-mediated (neddylation) pathways underlined ARVD/C as CSN6 binding, localization, levels and function were impacted in hearts of classic ARVD/C mouse models and ARVD/C patients impacted by desmosomal loss and mutations, respectively. We anticipate our findings have broad implications towards understanding mechanisms driving desmosome degradation in other desmosomal-based diseases, such as cancers.

Structure and function of DHHC protein S-acyltransferases

2017 ◽  
Vol 45 (4) ◽  
pp. 923-928 ◽  
Author(s):  
Colin D. Gottlieb ◽  
Maurine E. Linder
Keyword(s):  
Mouse Models ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Protein S ◽  
Structure And Function ◽  
Deficient Mouse ◽  
Enzymatic Function ◽  
Cytoplasmic Face ◽  
Dhhc Protein ◽  
And Function

It has been estimated that 10% of the human genome encodes proteins that are fatty acylated at cysteine residues. The vast majority of these proteins are modified by members of the DHHC protein family, which carry out their enzymatic function on the cytoplasmic face of cell membranes. The biomedical importance of DHHC proteins is underscored by their association with human disease; unique and essential roles for DHHC proteins have been uncovered using DHHC-deficient mouse models. Accordingly, there is great interest in elucidating the molecular mechanisms that underlie DHHC protein function. In this review, we present recent insights into the structure and function of DHHC enzymes.

scholarly journals From Exosome Glycobiology to Exosome Glycotechnology, the Role of Natural Occurring Polysaccharides

2021 ◽  
Vol 2 (2) ◽  
pp. 311-338
Author(s):  
Giulia Della Rosa ◽  
Clarissa Ruggeri ◽  
Alessandra Aloisi
Keyword(s):  
State Of The Art ◽  
Cell Communication ◽  
Pathological Conditions ◽  
New Findings ◽  
Cell Type Specific ◽  
New Perspective ◽  
And Function ◽  
And Personalized Medicine ◽  
Innate Ability

Exosomes (EXOs) are nano-sized informative shuttles acting as endogenous mediators of cell-to-cell communication. Their innate ability to target specific cells and deliver functional cargo is recently claimed as a promising theranostic strategy. The glycan profile, actively involved in the EXO biogenesis, release, sorting and function, is highly cell type-specific and frequently altered in pathological conditions. Therefore, the modulation of EXO glyco-composition has recently been considered an attractive tool in the design of novel therapeutics. In addition to the available approaches involving conventional glyco-engineering, soft technology is becoming more and more attractive for better exploiting EXO glycan tasks and optimizing EXO delivery platforms. This review, first, explores the main functions of EXO glycans and associates the potential implications of the reported new findings across the nanomedicine applications. The state-of-the-art of the last decade concerning the role of natural polysaccharides—as targeting molecules and in 3D soft structure manufacture matrices—is then analysed and highlighted, as an advancing EXO biofunction toolkit. The promising results, integrating the biopolymers area to the EXO-based bio-nanofabrication and bio-nanotechnology field, lay the foundation for further investigation and offer a new perspective in drug delivery and personalized medicine progress.

Are gap junctions necessary for cell-to-cell coupling of smooth muscle?: an update

1992 ◽  
Vol 70 (4) ◽  
pp. 481-490 ◽  
Author(s):  
R. E. Garfield ◽  
G. Thilander ◽  
M. G. Blennerhassett ◽  
N. Sakai
Keyword(s):  
Smooth Muscle ◽  
Gap Junctions ◽  
Current Knowledge ◽  
Smooth Muscles ◽  
Cell Communication ◽  
Circular Muscle ◽  
Cell Coupling ◽  
And Function ◽  
Longitudinal Layer ◽  
Cell Cell

Earlier, it was questioned whether gap junctions (GJs) were necessary for cell–cell communication in smooth muscle, and GJs were not seen in some smooth muscles. We reexamined this question in the myometrium and in intestinal smooth muscle, in light of current knowledge of the presence and function of GJs. In the uterus, numerous studies show that an increase in GJ number is associated with the onset of delivery and is required for effective parturition. In all cases, this increase in GJ number and the changes in uterine contractility were correlated with increased electrical and metabolic coupling. Evidence for the much smaller, but detectable, degree of electrical coupling in the preterm uterus is explained by the small (but again detectable) number of GJs present. In the intestine, GJs are readily detected in the circular muscle layer but have not been described in the adjacent longitudinal layer. While our immunohistochemical studies failed to detect GJs in the longitudinal layer, this may not be adequate to prove their absence. Therefore, current knowledge of GJ number and function is adequate to explain cell–cell coupling in the uterus. Although it remains uncertain whether GJs are absent from the longitudinal muscle of the intestine, there is no definitive evidence that cell–cell coupling can occur by means other than GJs.Key words: gap junctions, myometrium, connexins, smooth muscle, cell communication.

scholarly journals Extracellular chloride signals collagen IV network assembly during basement membrane formation

2016 ◽  
Vol 213 (4) ◽  
pp. 479-494 ◽  
Author(s):  
Christopher F. Cummings ◽  
Vadim Pedchenko ◽  
Kyle L. Brown ◽  
Selene Colon ◽  
Mohamed Rafi ◽  
...  
Keyword(s):  
Cell Culture ◽  
Basement Membrane ◽  
Collagen Iv ◽  
Atomic Level ◽  
Basement Membranes ◽  
Tissue Architecture ◽  
Dynamic Interactions ◽  
Conformational Switch ◽  
And Function ◽  
Fundamental Mechanism

Basement membranes are defining features of the cellular microenvironment; however, little is known regarding their assembly outside cells. We report that extracellular Cl− ions signal the assembly of collagen IV networks outside cells by triggering a conformational switch within collagen IV noncollagenous 1 (NC1) domains. Depletion of Cl− in cell culture perturbed collagen IV networks, disrupted matrix architecture, and repositioned basement membrane proteins. Phylogenetic evidence indicates this conformational switch is a fundamental mechanism of collagen IV network assembly throughout Metazoa. Using recombinant triple helical protomers, we prove that NC1 domains direct both protomer and network assembly and show in Drosophila that NC1 architecture is critical for incorporation into basement membranes. These discoveries provide an atomic-level understanding of the dynamic interactions between extracellular Cl− and collagen IV assembly outside cells, a critical step in the assembly and organization of basement membranes that enable tissue architecture and function. Moreover, this provides a mechanistic framework for understanding the molecular pathobiology of NC1 domains.

scholarly journals Severity of Demyelinating and Axonal Neuropathy Mouse Models Is Modified by Genes Affecting Structure and Function of Peripheral Nodes

Cell Reports ◽  
2017 ◽  
Vol 18 (13) ◽  
pp. 3178-3191 ◽  
Author(s):  
Kathryn H. Morelli ◽  
Kevin L. Seburn ◽  
David G. Schroeder ◽  
Emily L. Spaulding ◽  
Loiuse A. Dionne ◽  
...  
Keyword(s):  
Mouse Models ◽  
Axonal Neuropathy ◽  
Structure And Function ◽  
And Function

scholarly journals Cell Atlas technologies and insights into tissue architecture

2020 ◽  
Vol 477 (8) ◽  
pp. 1427-1442 ◽  
Author(s):  
Anna Wilbrey-Clark ◽  
Kenny Roberts ◽  
Sarah A. Teichmann
Keyword(s):  
Single Cell ◽  
Molecular Level ◽  
Cell Types ◽  
Tissue Architecture ◽  
Robert Hooke ◽  
Spatially Resolved ◽  
Gene And Protein Expression ◽  
Basic Biology ◽  
And Function ◽  
Fundamental Units

Since Robert Hooke first described the existence of ‘cells’ in 1665, scientists have sought to identify and further characterise these fundamental units of life. While our understanding of cell location, morphology and function has expanded greatly; our understanding of cell types and states at the molecular level, and how these function within tissue architecture, is still limited. A greater understanding of our cells could revolutionise basic biology and medicine. Atlasing initiatives like the Human Cell Atlas aim to identify all cell types at the molecular level, including their physical locations, and to make this reference data openly available to the scientific community. This is made possible by a recent technology revolution: both in single-cell molecular profiling, particularly single-cell RNA sequencing, and in spatially resolved methods for assessing gene and protein expression. Here, we review available and upcoming atlasing technologies, the biological insights gained to date and the promise of this field for the future.

scholarly journals The STAGA Subunit ADA2b Is an Important Regulator of Human GCN5 Catalysis

2008 ◽  
Vol 29 (1) ◽  
pp. 266-280 ◽  
Author(s):  
Armin M. Gamper ◽  
Jaehoon Kim ◽  
Robert G. Roeder
Keyword(s):  
Saga Complex ◽  
Histone Tails ◽  
Functional Roles ◽  
Enzymatic Function ◽  
Core Histones ◽  
Human Proteins ◽  
Important Regulator ◽  
And Function

ABSTRACT Human STAGA is a multisubunit transcriptional coactivator containing the histone acetyltransferase GCN5L. Previous studies of the related yeast SAGA complex have shown that the yeast Gcn5, Ada2, and Ada3 components form a heterotrimer that is important for the enzymatic function of SAGA. Here, we report that ADA2a and ADA2b, two human homologues of yeast Ada2, each have the ability to form a heterotrimer with ADA3 and GCN5L but that only the ADA2b homologue is found in STAGA. By comparing the patterns of acetylation of several substrates, we found context-dependent requirements for ADA2b and ADA3 for the efficient acetylation of histone tails by GCN5. With human proteins, unlike yeast proteins, the acetylation of free core histones by GCN5 is unaffected by ADA2b or ADA3. In contrast, the acetylation of mononucleosomal substrates by GCN5 is enhanced by ADA2b, with no significant additional effect of ADA3, and the efficient acetylation of nucleosomal arrays (chromatin) by GCN5 requires both ADA2b and ADA3. Thus, ADA2b and ADA3 appear to act at two different levels of histone organization within chromatin to facilitate GCN5 function. Interestingly, although ADA2a forms a complex(es) with GCN5 and ADA3 both in vitro and in vivo, ADA2a-containing complexes are unable to acetylate nucleosomal H3. We have also shown the preferential recruitment of ADA2b, relative to ADA2a, to p53-dependent genes. This finding indicates that the previously demonstrated presence and function of GCN5 on these promoters reflect the action of STAGA and that the ADA2a and ADA2b paralogues have nonredundant functional roles.

Stress Echocardiography

2018 ◽  
pp. 326-334
Author(s):  
L. Samuel Wann
Keyword(s):  
Cardiac Disease ◽  
Stress Echocardiography ◽  
Comprehensive Evaluation ◽  
Structure And Function ◽  
Cardiac Structure ◽  
Ultrasound Assessment ◽  
Cardiac Structure And Function ◽  
Artery Disease ◽  
Sensitivity Specificity ◽  
And Function

The Stress Echocardiography chapter reviews the opportunities to increase sensitivity and specificity of stress testing for the diagnosis of ischemic heart disease with adjunctive echocardiography with exercise or dobutamine-atropine stress. Baseline imaging prior to stress should include a comprehensive evaluation of cardiac structure and function, including the assessment of valvular disease with Doppler echocardiography. The chapter discusses stress echocardiography protocols; image analysis and reporting; sensitivity, specificity, and accuracy for detection of coronary artery disease; and evaluation of noncoronary cardiac disease. New and developing echocardiographic technology, including ultrasound assessment of myocardial perfusion, real-time 3D echocardiographic, and strain imaging are also discussed.

scholarly journals Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome

2020 ◽  
Vol 21 (18) ◽  
pp. 6906
Author(s):  
Carmen Martínez-Cué ◽  
Noemí Rueda
Keyword(s):  
Down Syndrome ◽  
Tau Protein ◽  
Amyloid Plaques ◽  
Feedback Mechanism ◽  
Signalling Pathways ◽  
Protein Loss ◽  
Sporadic Alzheimer’S Disease ◽  
Genetic Origin ◽  
Fourth Decade ◽  
And Function

Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.

scholarly journals Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

2019 ◽  
Vol 21 (1) ◽  
pp. 266 ◽  
Author(s):  
Gabriella Schiera ◽  
Carlo Maria Di Liegro ◽  
Italia Di Liegro
Keyword(s):  
Learning And Memory ◽  
Extracellular Vesicles ◽  
Glial Cells ◽  
Information Exchange ◽  
System Development ◽  
Cell Communication ◽  
Nervous System Development ◽  
The Body ◽  
Pathological Conditions ◽  
And Function

Most aspects of nervous system development and function rely on the continuous crosstalk between neurons and the variegated universe of non-neuronal cells surrounding them. The most extraordinary property of this cellular community is its ability to undergo adaptive modifications in response to environmental cues originating from inside or outside the body. Such ability, known as neuronal plasticity, allows long-lasting modifications of the strength, composition and efficacy of the connections between neurons, which constitutes the biochemical base for learning and memory. Nerve cells communicate with each other through both wiring (synaptic) and volume transmission of signals. It is by now clear that glial cells, and in particular astrocytes, also play critical roles in both modes by releasing different kinds of molecules (e.g., D-serine secreted by astrocytes). On the other hand, neurons produce factors that can regulate the activity of glial cells, including their ability to release regulatory molecules. In the last fifteen years it has been demonstrated that both neurons and glial cells release extracellular vesicles (EVs) of different kinds, both in physiologic and pathological conditions. Here we discuss the possible involvement of EVs in the events underlying learning and memory, in both physiologic and pathological conditions.

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