scholarly journals Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity

2018 ◽  
Author(s):  
Melanie Schauer ◽  
Kristina J H Kleinwort ◽  
Roxane L Degroote ◽  
Carmen Wiedemann ◽  
Elisabeth Kremmer ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Cell Shape ◽  
Interaction Network ◽  
Immune Functions ◽  
Cytoskeleton Organization ◽  
Cellular Processes ◽  
Network Interaction ◽  
Interaction Proteomics ◽  
Spontaneous Animal Model

ABSTRACTThe GTP-binding protein septin 7 is involved in various cellular processes, including cytoskeleton organization, migration and the regulation of cell shape. Septin 7 function in lymphocytes, however, is poorly characterized. Since the intracellular signaling role of septin 7 is dependent on its interaction network, interaction proteomics was applied to attain novel knowledge about septin 7 function in hematopoietic cells. Our previous finding of decreased septin 7 expression in blood-derived lymphocytes in ERU, a spontaneous animal model for autoimmune uveitis in man, extended the role of septin 7 to a potential key player in autoimmunity. Here, we revealed novel insights into septin 7 function by identification of DOCK8 as an interaction partner in primary blood-derived lymphocytes. Since DOCK8 is associated with important immune functions, our finding of significantly decreased DOCK8 expression and altered DOCK8 interaction network in ERU might explain changes in immune response and shows the contribution of DOCK8 in pathomechanisms of spontaneous autoimmune diseases. Moreover, our analyses revealed insights in DOCK8 function, by identifying the signal transducer ILK as a DOCK8 interactor in lymphocytes. Our finding of the enhanced enrichment of ILK in ERU cases indicates a deviant influence of DOCK8 on inter- and intracellular signaling in autoimmune disease.

scholarly journals Lysosome Function in Cardiovascular Diseases

2021 ◽  
Vol 55 (3) ◽  
pp. 277-300
Keyword(s):  
Intracellular Signaling ◽  
Hydrolytic Enzymes ◽  
Vascular Diseases ◽  
Sphingolipid Metabolism ◽  
Cellular Behavior ◽  
Cellular Processes ◽  
Vascular Regulation ◽  
Large Numbers ◽  
And Function

The lysosome is a single ubiquitous membrane-enclosed intracellular organelle with an acidic pH present in all eukaryotic cells, which contains large numbers of hydrolytic enzymes with their maximal enzymatic activity at a low pH (pH ≤ 5) such as proteases, nucleases, and phosphatases that are able to degrade extracellular and intracellular components. It is well known that lysosomes act as a center for degradation and recycling of large numbers of macromolecules delivered by endocytosis, phagocytosis, and autophagy. Lysosomes are recognized as key organelles for cellular clearance and are involved in many cellular processes and maintain cellular homeostasis. Recently, it has been shown that lysosome function and its related pathways are of particular importance in vascular regulation and related diseases. In this review, we highlighted studies that have improved our understanding of the connection between lysosome function and vascular physiological and pathophysiological activities in arterial smooth muscle cells (SMCs) and endothelial cells (ECs). Sphingolipids-metabolizingenzymes in lysosomes play critical roles in intracellular signaling events that influence cellular behavior and function in SMCs and ECs. The focus of this review will be to define the mechanism by which the lysosome contributes to cardiovascular regulation and diseases. It is believed that exploring the role of lysosomal function and its sphingolipid metabolism in the initiation and progression of vascular disease and regulation may provide novel insights into the understanding of vascular pathobiology and helps develop more effective therapeutic strategies for vascular diseases.

Role of plectin in cytoskeleton organization and dynamics

1998 ◽  
Vol 111 (17) ◽  
pp. 2477-2486 ◽  
Author(s):  
G. Wiche
Keyword(s):  
Strong Support ◽  
Cell Types ◽  
Hereditary Disease ◽  
Epidermolysis Bullosa Simplex ◽  
Cytoskeleton Organization ◽  
Cellular Processes ◽  
Cytoskeletal Filament ◽  
Filament Networks

Plectin and its isoforms are versatile cytoskeletal linker proteins of very large size (>500 kDa) that are abundantly expressed in a wide variety of mammalian tissues and cell types. Earlier studies indicated that plectin molecules were associated with and/or directly bound to subcomponents of all three major cytoskeletal filament networks, the subplasma membrane protein skeleton, and a variety of plasma membrane-cytoskeleton junctional complexes, including those found in epithelia, various types of muscle, and fibroblasts. In conjunction with biochemical data, this led to the concept that plectin plays an important role in cytoskeleton network organization, with consequences for viscoelastic properties of the cytoplasm and the mechanical integrity and resistance of cells and tissues. Several recent findings lent strong support to this concept. One was that a hereditary disease, epidermolysis bullosa simplex (EBS)-MD, characterized by severe skin blistering combined with muscular dystrophy, is caused by defects in the plectin gene. Another was the generation of plectin-deficient mice by targeted inactivation of the gene. Dying shortly after birth, these animals exhibited severe defects in skin, skeletal muscle and heart. Moreover, in vitro studies with cells derived from such animals unmasked an essential new role of plectin as regulator of cellular processes involving actin stress fibers dynamics. Comprehensive analyses of the gene locus in man, mouse, and rat point towards a complex gene expression machinery, comprising an unprecedented diversity of differentially spliced transcripts with distinct 5′ starting exons, probably regulated by different promoters. This could provide a basis for cell type-dependent and/or developmentally-controlled expression of plectin isoforms, exerting different functions through binding to distinct partners. Based on its versatile functions and structural diversification plectin emerges as a prototype cytolinker protein among a family of proteins sharing partial structural homology and functions.

scholarly journals Presenilins and γ-Secretase in Membrane Proteostasis

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 209 ◽  
Author(s):  
Naoto Oikawa ◽  
Jochen Walter
Keyword(s):  
Membrane Protein ◽  
Protein Metabolism ◽  
Intracellular Signaling ◽  
Functional Relation ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Cellular Functions ◽  
Homologous Proteins ◽  
Cellular Processes

The presenilin (PS) proteins exert a crucial role in the pathogenesis of Alzheimer disease (AD) by mediating the intramembranous cleavage of amyloid precursor protein (APP) and the generation of amyloid β-protein (Aβ). The two homologous proteins PS1 and PS2 represent the catalytic subunits of distinct γ-secretase complexes that mediate a variety of cellular processes, including membrane protein metabolism, signal transduction, and cell differentiation. While the intramembrane cleavage of select proteins by γ-secretase is critical in the regulation of intracellular signaling pathways, the plethora of identified protein substrates could also indicate an important role of these enzyme complexes in membrane protein homeostasis. In line with this notion, PS proteins and/or γ-secretase has also been implicated in autophagy, a fundamental process for the maintenance of cellular functions and homeostasis. Dysfunction in the clearance of proteins in the lysosome and during autophagy has been shown to contribute to neurodegeneration. This review summarizes the recent knowledge about the role of PS proteins and γ-secretase in membrane protein metabolism and trafficking, and the functional relation to lysosomal activity and autophagy.

scholarly journals LncRNA HOTAIR in Tumor Microenvironment: What Role?

2019 ◽  
Vol 20 (9) ◽  
pp. 2279 ◽  
Author(s):  
Gerardo Botti ◽  
Giosuè Scognamiglio ◽  
Gabriella Aquino ◽  
Giuseppina Liguori ◽  
Monica Cantile
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Intracellular Signaling ◽  
Regulation Of Gene Expression ◽  
Tumor Evolution ◽  
Metastatic Progression ◽  
Cellular Processes ◽  
Cellular Components ◽  
Lncrna Hotair

lncRNAs participate in many cellular processes, including regulation of gene expression at the transcriptional and post-transcriptional levels. In addition, many lncRNAs can contribute to the development of different human diseases including cancer. The tumor microenvironment (TME) plays an important role during tumor growth and metastatic progression, and most of these lncRNAs have a key function in TME intracellular signaling. Among the numerous identified lncRNAs, several experimental evidences have shown the fundamental role of the lncRNA HOTAIR in carcinogenesis, also highlighting its use as a circulating biomarker. In this review we described the contribution of HOTAIR in the TME modulation, highlighting its relation with cellular and non-cellular components during tumor evolution and progression.

scholarly journals Role of GLI Transcription Factors in Pathogenesis and Their Potential as New Therapeutic Targets

2018 ◽  
Vol 19 (9) ◽  
pp. 2562 ◽  
Author(s):  
Maja Sabol ◽  
Diana Trnski ◽  
Vesna Musani ◽  
Petar Ozretić ◽  
Sonja Levanat
Keyword(s):  
Transcription Factors ◽  
Intracellular Signaling ◽  
Developmental Pathways ◽  
Cellular Processes ◽  
Gli Transcription Factors ◽  
Intracellular Signaling Cascade ◽  
Adult Organism ◽  
Therapeutic Protocols ◽  
Deregulated Pathway

GLI transcription factors have important roles in intracellular signaling cascade, acting as the main mediators of the HH-GLI signaling pathway. This is one of the major developmental pathways, regulated both canonically and non-canonically. Deregulation of the pathway during development leads to a number of developmental malformations, depending on the deregulated pathway component. The HH-GLI pathway is mostly inactive in the adult organism but retains its function in stem cells. Aberrant activation in adult cells leads to carcinogenesis through overactivation of several tightly regulated cellular processes such as proliferation, angiogenesis, EMT. Targeting GLI transcription factors has recently become a major focus of potential therapeutic protocols.

scholarly journals PFN2 and NAA80 cooperate to efficiently acetylate the N-terminus of actin

2020 ◽  
Vol 295 (49) ◽  
pp. 16713-16731 ◽  
Author(s):  
Rasmus Ree ◽  
Laura Kind ◽  
Anna Kaziales ◽  
Sylvia Varland ◽  
Minglu Dai ◽  
...  
Keyword(s):  
Cell Shape ◽  
Analytical Ultracentrifugation ◽  
Enzyme Assays ◽  
Modus Operandi ◽  
X Ray ◽  
X Ray Scattering ◽  
N Terminus ◽  
Cytoskeletal Dynamics ◽  
Interaction Proteomics

The actin cytoskeleton is of profound importance to cell shape, division, and intracellular force generation. Profilins bind to globular (G-)actin and regulate actin filament formation. Although profilins are well-established actin regulators, the distinct roles of the dominant profilin, profilin 1 (PFN1), versus the less abundant profilin 2 (PFN2) remain enigmatic. In this study, we use interaction proteomics to discover that PFN2 is an interaction partner of the actin N-terminal acetyltransferase NAA80, and further confirm this by analytical ultracentrifugation. Enzyme assays with NAA80 and different profilins demonstrate that PFN2 binding specifically increases the intrinsic catalytic activity of NAA80. NAA80 binds PFN2 through a proline-rich loop, deletion of which abrogates PFN2 binding. Small-angle X-ray scattering shows that NAA80, actin, and PFN2 form a ternary complex and that NAA80 has partly disordered regions in the N-terminus and the proline-rich loop, the latter of which is partly ordered upon PFN2 binding. Furthermore, binding of PFN2 to NAA80 via the proline-rich loop promotes binding between the globular domains of actin and NAA80, and thus acetylation of actin. However, the majority of cellular NAA80 is stably bound to PFN2 and not to actin, and we propose that this complex acetylates G-actin before it is incorporated into filaments. In conclusion, we reveal a functionally specific role of PFN2 as a stable interactor and regulator of the actin N-terminal acetyltransferase NAA80, and establish the modus operandi for NAA80-mediated actin N-terminal acetylation, a modification with a major impact on cytoskeletal dynamics.

scholarly journals Notch Signaling Regulation in Autoinflammatory Diseases

2020 ◽  
Vol 21 (22) ◽  
pp. 8847
Author(s):  
Rossella Gratton ◽  
Paola Maura Tricarico ◽  
Adamo Pio d'Adamo ◽  
Anna Monica Bianco ◽  
Ronald Moura ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Notch Pathway ◽  
Autoinflammatory Diseases ◽  
Cellular Processes ◽  
Core Components

Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.

scholarly journals The Role of Cell Adhesion and Cytoskeleton Dynamics in the Pathogenesis of the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Sabeeha Malek ◽  
Darius V. Köster
Keyword(s):  
Extracellular Matrix ◽  
Cell Adhesion ◽  
Genetic Basis ◽  
Joint Hypermobility ◽  
Cytoskeleton Organization ◽  
Cellular Processes ◽  
Membrane Bound ◽  
Spectrum Disorders ◽  
Cytoskeleton Dynamics

The Ehlers-Danlos syndromes (EDS) are a group of 13 disorders, clinically defined through features of joint hypermobility, skin hyperextensibility, and tissue fragility. Most subtypes are caused by mutations in genes affecting the structure or processing of the extracellular matrix (ECM) protein collagen. The Hypermobility Spectrum Disorders (HSDs) are clinically indistinguishable disorders, but are considered to lack a genetic basis. The pathogenesis of all these disorders, however, remains poorly understood. Genotype-phenotype correlations are limited, and findings of aberrant collagen fibrils are inconsistent and associate poorly with the subtype and severity of the disorder. The defective ECM, however, also has consequences for cellular processes. EDS/HSD fibroblasts exhibit a dysfunctional phenotype including impairments in cell adhesion and cytoskeleton organization, though the pathological significance of this has remained unclear. Recent advances in our understanding of fibroblast mechanobiology suggest these changes may actually reflect features of a pathomechanism we herein define. This review departs from the traditional view of EDS/HSD, where pathogenesis is mediated by the structurally defective ECM. Instead, we propose EDS/HSD may be a disorder of membrane-bound collagen, and consider how aberrations in cell adhesion and cytoskeleton dynamics could drive the abnormal properties of the connective tissue, and be responsible for the pathogenesis of EDS/HSD.

scholarly journals Determination of nuclear position by the arrangement of actin filaments using deep generative networks

2021 ◽  
Author(s):  
Jyothsna Vasudevan ◽  
Chuanxia Zheng ◽  
James G Wan ◽  
Tat-Jen Cham ◽  
Chwee Teck Lim ◽  
...  
Keyword(s):  
Actin Filaments ◽  
Structural Integrity ◽  
Data Augmentation ◽  
Dynamic Structure ◽  
Nuclear Position ◽  
Cytoskeleton Organization ◽  
Cellular Processes ◽  
Level Of Significance

The cell nucleus is a dynamic structure that changes locales during cellular processes such as proliferation, differentiation, or migration, and its mispositioning is a hallmark of several disorders. As with most mechanobiological activities of adherent cells, the repositioning and anchoring of the nucleus are presumed to be associated with the organization of the cytoskeleton, the network of protein filaments providing structural integrity to the cells. However, this correlation between cytoskeleton organization and nuclear position has not, to date, been demonstrated, as it would require the parameterization of the extraordinarily intricate cytoskeletal fiber arrangements. Here, we show that this parameterization and demonstration can be achieved outside the limits of human conceptualization, using generative network and raw microscope images, relying on machine-driven interpretation and selection of parameterizable features. The developed transformer-based architecture was able to generate high-quality, completed images of more than 8,000 cells, using only information on actin filaments, predicting the presence of a nucleus and its exact localization in more than 70 per cent of instances. Our results demonstrate one of the most basic principles of mechanobiology with a remarkable level of significance. They also highlight the role of deep learning as a powerful tool in biology beyond data augmentation and analysis, capable of interpreting -unconstrained by the principles of human reasoning- complex biological systems from qualitative data.

scholarly journals Pulsed actomyosin contractions in morphogenesis

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 142 ◽  
Author(s):  
Ann Sutherland ◽  
Alyssa Lesko
Keyword(s):  
Cell Shape ◽  
Normal Development ◽  
Tissue Growth ◽  
Model Systems ◽  
Cellular Processes ◽  
Cytoskeletal Networks ◽  
And Migration ◽  
Shape Changes

Cell and tissue shape changes are the fundamental elements of morphogenesis that drive normal development of embryos into fully functional organisms. This requires a variety of cellular processes including establishment and maintenance of polarity, tissue growth and apoptosis, and cell differentiation, rearrangement, and migration. It is widely appreciated that the cytoskeletal networks play an important role in regulating many of these processes and, in particular, that pulsed actomyosin contractions are a core cellular mechanism driving cell shape changes and cell rearrangement. In this review, we discuss the role of pulsed actomyosin contractions during developmental morphogenesis, advances in our understanding of the mechanisms regulating actomyosin pulsing, and novel techniques to probe the role of pulsed actomyosin processes in in vivo model systems.

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