scholarly journals Heparan Sulfated Glypican-4 is Released from Astrocytes Predominantly by Proteolytic Shedding

2021 ◽  
Author(s):  
Kevin Huang ◽  
Sungjin Park
Keyword(s):  
Synapse Formation ◽  
Regulatory Mechanism ◽  
Active Form ◽  
Release Mechanism ◽  
Loss Of Function ◽  
Secreted Factors ◽  
Release Mechanisms ◽  
Synapse Maturation ◽  
And Function ◽  
Proteolytic Shedding

AbstractAstrocytes provide neurons with diffusible factors that promote synapse formation and maturation. In particular, glypican-4/GPC4 released from astrocytes promotes the maturation of excitatory synapses. Unlike other secreted factors, GPC4 contains the C-terminal GPI-anchorage signal. However, the mechanism by which membrane-tethered GPC4 is released from astrocytes is unknown. Using primary astrocyte cultures and a quantitative luciferase-based release assay, we show that GPC4 is expressed on the astrocyte surface exclusively via a GPI-anchorage. Soluble GPC4 is robustly released from the astrocytes predominantly by proteolytic shedding and, to a lesser extent, by GPI-anchor cleavage, but not by vesicular release. Pharmacological, overexpression, and loss of function screens showed that ADAM9 in part mediates the release of GPC4 from astrocytes. The released GPC4 contains the heparan sulfate side chain, suggesting that these release mechanisms provide the active form that promotes synapse maturation and function. Overall, our studies identified the release mechanisms and the major releasing enzyme of GPC4 in astrocytes and will provide insights into understanding how astrocytes regulate synapse formation and maturation.Significance StatementAstrocyte-derived diffusible factors regulate synapse development and function. However, the regulatory mechanism underlying the release of astrocyte-derived factors is poorly understood. Noting that, unlike many other secreted factors, glypican-4/GPC4 is GPI-anchored, we characterized the release mechanism of GPI-anchored GPC4 from astrocytes and identified the releasing enzyme. Heparan sulfated GPC4 is robustly released from the astrocytes predominantly by proteolytic shedding. In particular, ADAM9 in part mediates the release of GPC4 from astrocytes. Our study provides an enzymatic mechanism for releasing GPC4 from astrocytes and will provide a novel opportunity to understand the regulatory mechanism of neuron-glia communication for synaptogenesis.

Liprin-α proteins: scaffold molecules for synapse maturation

2007 ◽  
Vol 35 (5) ◽  
pp. 1278-1282 ◽  
Author(s):  
S.A. Spangler ◽  
C.C. Hoogenraad
Keyword(s):  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Synaptic Proteins ◽  
Model Systems ◽  
Scaffolding Proteins ◽  
Synapse Maturation ◽  
Biochemical Genetic ◽  
Processing And Storage ◽  
And Function ◽  
And Storage

Synapses are specialized communication junctions between neurons whose plasticity provides the structural and functional basis for information processing and storage in the brain. Recent biochemical, genetic and imaging studies in diverse model systems are beginning to reveal the molecular mechanisms by which synaptic vesicles, ion channels, receptors and other synaptic components assemble to make a functional synapse. Recent evidence has shown that the formation and function of synapses are critically regulated by the liprin-α family of scaffolding proteins. The liprin-αs have been implicated in pre- and post-synaptic development by recruiting synaptic proteins and regulating synaptic cargo transport. Here, we will summarize the diversity of liprin binding partners, highlight the factors that control the function of liprin-αs at the synapse and discuss how liprin-α family proteins regulate synapse formation and synaptic transmission.

scholarly journals β1A Integrin Is a Master Regulator of Invadosome Organization and Function

2010 ◽  
Vol 21 (23) ◽  
pp. 4108-4119 ◽  
Author(s):  
Olivier Destaing ◽  
Emmanuelle Planus ◽  
Daniel Bouvard ◽  
Christiane Oddou ◽  
Cedric Badowski ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Active Form ◽  
Focal Adhesions ◽  
Cell Types ◽  
Actin Dynamics ◽  
Loss Of Function ◽  
Protein Kinase C Activity ◽  
New Strategy ◽  
Ecm Degradation ◽  
And Function

Invadosomes are adhesion structures involved in tissue invasion that are characterized by an intense actin polymerization–depolymerization associated with β1 and β3 integrins and coupled to extracellular matrix (ECM) degradation activity. We induced the formation of invadosomes by expressing the constitutive active form of Src, SrcYF, in different cell types. Use of ECM surfaces micropatterned at the subcellular scale clearly showed that in mesenchymal cells, integrin signaling controls invadosome activity. Using β1−/− or β3−/− cells, it seemed that β1A but not β3 integrins are essential for initiation of invadosome formation. Protein kinase C activity was shown to regulate autoassembly of invadosomes into a ring-like metastructure (rosette), probably by phosphorylation of Ser785 on the β1A tail. Moreover, our study clearly showed that β1A links actin dynamics and ECM degradation in invadosomes. Finally, a new strategy based on fusion of the photosensitizer KillerRed to the β1A cytoplasmic domain allowed specific and immediate loss of function of β1A, resulting in disorganization and disassembly of invadosomes and formation of focal adhesions.

Matrix Metalloproteinases in Invertebrates

2020 ◽  
Vol 27 (11) ◽  
pp. 1068-1081
Author(s):  
Xi Liu ◽  
Dongwu Liu ◽  
Yangyang Shen ◽  
Mujie Huang ◽  
Lili Gao ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Immune Responses ◽  
Theoretical Basis ◽  
Regulatory Mechanism ◽  
Structure And Function ◽  
Catalytic Domains ◽  
Physiological Processes ◽  
Disease Occurrence ◽  
Complex Functions ◽  
And Function

Matrix Metalloproteinases (MMPs) belong to a family of metal-dependent endopeptidases which contain a series of conserved pro-peptide domains and catalytic domains. MMPs have been widely found in plants, animals, and microorganisms. MMPs are involved in regulating numerous physiological processes, pathological processes, and immune responses. In addition, MMPs play a key role in disease occurrence, including tumors, cardiovascular diseases, and other diseases. Compared with invertebrate MMPs, vertebrate MMPs have diverse subtypes and complex functions. Therefore, it is difficult to study the function of MMPs in vertebrates. However, it is relatively easy to study invertebrate MMPs because there are fewer subtypes of MMPs in invertebrates. In the present review, the structure and function of MMPs in invertebrates were summarized, which will provide a theoretical basis for investigating the regulatory mechanism of MMPs in invertebrates.

scholarly journals Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrian Israel Lehvy ◽  
Guy Horev ◽  
Yarden Golan ◽  
Fabian Glaser ◽  
Yael Shammai ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Zinc Homeostasis ◽  
Healthy Population ◽  
Missense Mutations ◽  
Protein Alignment ◽  
Loss Of Function ◽  
Intracellular Zinc ◽  
Dismal Prognosis ◽  
Zinc Levels ◽  
And Function

Abstract Zinc is vital for the structure and function of ~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

scholarly journals Maturation of the Na,K-ATPase in the Endoplasmic Reticulum in Health and Disease

2021 ◽  
Author(s):  
Vitalii Kryvenko ◽  
Olga Vagin ◽  
Laura A. Dada ◽  
Jacob I. Sznajder ◽  
István Vadász
Keyword(s):  
Endoplasmic Reticulum ◽  
Intracellular Signaling ◽  
Loss Of Function ◽  
Α Subunit ◽  
Rate Limiting Step ◽  
Atpase Subunits ◽  
A Cell ◽  
Health And Disease ◽  
And Function ◽  
Rate Limiting

Abstract The Na,K-ATPase establishes the electrochemical gradient of cells by driving an active exchange of Na+ and K+ ions while consuming ATP. The minimal functional transporter consists of a catalytic α-subunit and a β-subunit with chaperon activity. The Na,K-ATPase also functions as a cell adhesion molecule and participates in various intracellular signaling pathways. The maturation and trafficking of the Na,K-ATPase include co- and post-translational processing of the enzyme in the endoplasmic reticulum (ER) and the Golgi apparatus and subsequent delivery to the plasma membrane (PM). The ER folding of the enzyme is considered as the rate-limiting step in the membrane delivery of the protein. It has been demonstrated that only assembled Na,K-ATPase α:β-complexes may exit the organelle, whereas unassembled, misfolded or unfolded subunits are retained in the ER and are subsequently degraded. Loss of function of the Na,K-ATPase has been associated with lung, heart, kidney and neurological disorders. Recently, it has been shown that ER dysfunction, in particular, alterations in the homeostasis of the organelle, as well as impaired ER-resident chaperone activity may impede folding of Na,K-ATPase subunits, thus decreasing the abundance and function of the enzyme at the PM. Here, we summarize our current understanding on maturation and subsequent processing of the Na,K-ATPase in the ER under physiological and pathophysiological conditions. Graphic Abstract

scholarly journals Experimental CanSat Platform for Functional Verification of Burn Wire Triggering-Based Holding and Release Mechanisms

Aerospace ◽  
2021 ◽  
Vol 8 (7) ◽  
pp. 192
Author(s):  
Shankar Bhattarai ◽  
Ji-Seong Go ◽  
Hyun-Ung Oh
Keyword(s):  
Functional Performance ◽  
Flight Test ◽  
Easy Access ◽  
Functional Verification ◽  
Release Mechanism ◽  
Space Technology ◽  
Solar Panels ◽  
Distinctive Features ◽  
Release Mechanisms ◽  
Design Effectiveness

In this study, we present the Diverse Holding and Release Mechanism Can Satellite (DHRM CanSat) platform developed by the Space Technology Synthesis Laboratory (STSL) at Chosun University, South Korea. This platform focuses on several types of holding and release mechanisms (HRMs) for application in deployable appendages of nanosatellites. The objectives of the DHRM CanSat mission are to demonstrate the design effectiveness and functionality of the three newly proposed HRMs based on the burn wire triggering method, i.e., the pogo pin-type HRM, separation nut-type HRM, and Velcro tape-type HRM, which were implemented on deployable dummy solar panels of the CanSat. The proposed mechanisms have many advantages, including a high holding capability, simultaneous constraints in multi-plane directions, and simplicity of handling. Additionally, each mechanism has distinctive features, such as spring-loaded pins to initiate deployment, a plate with a thread as a nut for a high holding capability, and a hook and loop fastener for easy access to subsystems of the satellite without releasing the holding constraint. The design effectiveness and functional performance of the proposed mechanisms were demonstrated through an actual flight test of the DHRM CanSat launched by a model rocket.

scholarly journals Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

2021 ◽  
Author(s):  
Paolo Zanoni ◽  
Katharina Steindl ◽  
Deepanwita Sengupta ◽  
Pascal Joset ◽  
Angela Bahr ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Mild Phenotype ◽  
Psychological Issues ◽  
Missense Variants ◽  
Mild Developmental Delay ◽  
Pathogenic Variants ◽  
In Silico Modeling ◽  
And Function ◽  
Methylation Activity

Abstract Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.

scholarly journals New Tricks for an Old (Hedge)Hog: Sonic Hedgehog Regulation of Astrocyte Function

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1353
Author(s):  
A. Denise R. Garcia
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Synapse Formation ◽  
Inflammatory Responses ◽  
Molecular Signaling ◽  
Synaptic Organization ◽  
Shh Signaling ◽  
Broad Array ◽  
And Function ◽  
Molecular Signaling Pathway

The Sonic hedgehog (Shh) molecular signaling pathway is well established as a key regulator of neurodevelopment. It regulates diverse cellular behaviors, and its functions vary with respect to cell type, region, and developmental stage, reflecting the incredible pleiotropy of this molecular signaling pathway. Although it is best understood for its roles in development, Shh signaling persists into adulthood and is emerging as an important regulator of astrocyte function. Astrocytes play central roles in a broad array of nervous system functions, including synapse formation and function as well as coordination and orchestration of CNS inflammatory responses in pathological states. Neurons are the source of Shh in the adult, suggesting that Shh signaling mediates neuron–astrocyte communication, a novel role for this multifaceted pathway. Multiple roles for Shh signaling in astrocytes are increasingly being identified, including regulation of astrocyte identity, modulation of synaptic organization, and limitation of inflammation. This review discusses these novel roles for Shh signaling in regulating diverse astrocyte functions in the healthy brain and in pathology.

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