scholarly journals Multiple Targets for Oxysterols in Their Regulation of the Immune System

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2078
Author(s):  
Lisa Reinmuth ◽  
Cheng-Chih Hsiao ◽  
Jörg Hamann ◽  
Mette Rosenkilde ◽  
John Mackrill
Keyword(s):  
Immune System ◽  
Cell Surface ◽  
Oxidation Products ◽  
Epigenetic Mechanism ◽  
Cell Surface Receptor ◽  
Cholesterol Oxidation ◽  
Cell Surface Receptors ◽  
Cholesterol Oxidation Products ◽  
Surface Receptors ◽  
Cellular Processes

Oxysterols, or cholesterol oxidation products, are naturally occurring lipids which regulate the physiology of cells, including those of the immune system. In contrast to effects that are mediated through nuclear receptors or by epigenetic mechanism, which take tens of minutes to occur, changes in the activities of cell-surface receptors caused by oxysterols can be extremely rapid, often taking place within subsecond timescales. Such cell-surface receptor effects of oxysterols allow for the regulation of fast cellular processes, such as motility, secretion and endocytosis. These cellular processes play critical roles in both the innate and adaptive immune systems. This review will survey the two broad classes of cell-surface receptors for oxysterols (G-protein coupled receptors (GPCRs) and ion channels), the mechanisms by which cholesterol oxidation products act on them, and their presence and functions in the different cell types of the immune system. Overall, this review will highlight the potential of oxysterols, synthetic derivatives and their receptors for physiological and therapeutic modulation of the immune system.

scholarly journals Topological and Structural Plasticity of the Single Ig Fold and the Double Ig Fold Present in CD19

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1290 ◽  
Author(s):  
Philippe Youkharibache
Keyword(s):  
Cell Surface ◽  
3D Structure ◽  
Cell Surface Receptor ◽  
Cell Surface Receptors ◽  
Structural Domain ◽  
Surface Receptors ◽  
Surface Receptor ◽  
In Trans ◽  
In Cis ◽  
Ig Domain

The Ig fold has had a remarkable success in vertebrate evolution, with a presence in over 2% of human genes. The Ig fold is not just the elementary structural domain of antibodies and TCRs, it is also at the heart of a staggering 30% of immunologic cell surface receptors, making it a major orchestrator of cell–cell interactions. While BCRs, TCRs, and numerous Ig-based cell surface receptors form homo- or heterodimers on the same cell surface (in cis), many of them interface as ligand-receptors (checkpoints) on interacting cells (in trans) through their Ig domains. New Ig-Ig interfaces are still being discovered between Ig-based cell surface receptors, even in well-known families such as B7. What is largely ignored, however, is that the Ig fold itself is pseudosymmetric, a property that makes the Ig domain a versatile self-associative 3D structure and may, in part, explain its success in evolution, especially through its ability to bind in cis or in trans in the context of cell surface receptor–ligand interactions. In this paper, we review the Ig domains’ tertiary and quaternary pseudosymmetries, with particular attention to the newly identified double Ig fold in the solved CD19 molecular structure to highlight the underlying fundamental folding elements of Ig domains, i.e., Ig protodomains. This pseudosymmetric property of Ig domains gives us a decoding frame of reference to understand the fold, relate all Ig domain forms, single or double, and suggest new protein engineering avenues.

scholarly journals Reduction of leucocyte cell surface disulfide bonds during immune activation is dynamic as revealed by a quantitative proteomics workflow (SH-IQ)

Open Biology ◽  
2018 ◽  
Vol 8 (9) ◽  
pp. 180079
Author(s):  
Monika Stegmann ◽  
A. Neil Barclay ◽  
Clive Metcalfe
Keyword(s):  
Immune System ◽  
Cell Surface ◽  
Immune Activation ◽  
Disulfide Bonds ◽  
Cell Function ◽  
Immune Cell ◽  
Surface Proteins ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
Pathogen Clearance

Communication through cell surface receptors is crucial for maintaining immune homeostasis, coordinating the immune response and pathogen clearance. This is dependent on the interaction of cell surface receptors with their ligands and requires functionally active conformational states. Thus, immune cell function can be controlled by modulating the structure of either the receptor or the ligand. Reductive cleavage of labile disulfide bonds can mediate such an allosteric change, resulting in modulation of the immune system by a hitherto little studied mechanism. Identifying proteins with labile disulfide bonds and determining the extent of reduction is crucial in elucidating the functional result of reduction. We describe a mass spectrometry-based method—thiol identification and quantitation (SH-IQ)—to identify, quantify and monitor such reduction of labile disulfide bonds in primary cells during immune activation. These results provide the first insight into the extent and dynamics of labile disulfide bond reduction in leucocyte cell surface proteins upon immune activation. We show that this process is thiol oxidoreductase-dependent and mainly affects activatory (e.g. CD132, SLAMF1) and adhesion (CD44, ICAM1) molecules, suggesting a mechanism to prevent over-activation of the immune system and excessive accumulation of leucocytes at sites of inflammation.

scholarly journals Adenovirus Fiber Shaft Contains a Trimerization Element That Supports Peptide Fusion for Targeted Gene Delivery

2006 ◽  
Vol 80 (24) ◽  
pp. 12324-12331 ◽  
Author(s):  
Jiali Li ◽  
Sonya Lad ◽  
Guang Yang ◽  
Yunping Luo ◽  
Milena Iacobelli-Martinez ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Cell Surface ◽  
Chimeric Protein ◽  
Cell Surface Receptor ◽  
Cell Surface Receptors ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Surface Receptors ◽  
Fiber Assembly ◽  
Fiber Protein

ABSTRACT Adenoviral (Ad) vectors have been widely used in human gene therapy clinical trials. However, their application has frequently been restricted by the unfavorable expression of cell surface receptors critical for Ad infection. Infections by Ad2 and Ad5 are largely regulated by the elongated fiber protein that mediates its attachment to a cell surface receptor, coxsackie and adenovirus receptor (CAR). The fiber protein is a homotrimer consisting of an N-terminal tail, a long shaft, and a C-terminal knob region that is responsible for high-affinity receptor binding and Ad tropism. Consequently, the modification of the knob region, including peptide insertion and C-terminal fusion of ligands for cell surface receptors, has become a major research focus for targeting gene delivery. Such manipulation tends to disrupt fiber assembly since the knob region contains a stabilization element for fiber trimerization. We report here the identification of a novel trimerization element in the Ad fiber shaft. We demonstrate that fiber fragments containing the N-terminal tail and shaft repeats formed stable trimers that assembled onto Ad virions independently of the knob region. This fiber shaft trimerization element (FSTE) exhibited a capacity to support peptide fusion. We showed that Ad, modified with a chimeric protein by direct fusion of the FSTE with a growth factor ligand or a single-chain antibody, delivered a reporter gene selectively. Together, these results indicate that the shaft region of Ad fiber protein contains a trimerization element that allows ligand fusion, which potentially broadens the basis for Ad vector development.

scholarly journals Functional scintigraphy of the adrenal gland

2002 ◽  
Vol 147 (1) ◽  
pp. 13-28 ◽  
Author(s):  
D Rubello ◽  
C Bui ◽  
D Casara ◽  
MD Gross ◽  
LM Fig ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Cell Surface ◽  
Adrenal Cortex ◽  
Cell Surface Receptor ◽  
Cell Surface Receptors ◽  
Zona Fasciculata ◽  
Type I ◽  
Surface Receptors ◽  
Meta Iodo Benzyl Guanidine ◽  
And Storage

Over the last 30 years nuclear medicine imaging of the adrenal gland and its lesions has been achieved by the exploitation of a number of physiological characteristics of this organ. By seeking and utilising features which are quantitatively or qualitatively different from those of the adjacent tissues, functional depiction of the adrenal gland and its diseases, which in most cases retain the basic physiology of their tissue of origin, including both the cortex and the medulla, are now a useful clinical reality. Agents widely used in clinical practice include: (a) uptake and storage of radiolabelled cholesterol analogues via the low density lipoprotein (LDL) receptor and cholesterol ester storage pool in the adrenal cortex ((131)I-6-beta-iodomethyl-norcholesterol, (75)Se-selenomethyl-norcholesterol); (b) catecholamine type I, presynaptic, uptake mechanism and intracellular granule uptake and storage mechanism in the adrenal medulla and extra-adrenal paraganglia ((131)I-, (123)I- and (124)I-meta-iodo-benzyl-guanidine (MIBG), (18)F-metafluoro-benzyl-guanidine); (c) cell surface receptor binding of peptides/neurotransmitters/modulators such as for the family of five subtypes of somatostatin receptors ((123)I-tyr-octreotide, (111)In-DTPA-octreotide, (111)In-DOTA-octreotide and many others); (d) although not specific for the adrenal gland, increased glycolysis by tumours, particularly the most malignant varieties, (18)F-2-fluoro-d-deoxyglucose can thus be expected to depict certain malignant lesions such as malignant pheochromocytomas (particularly the minority which are not detected by MIBG) and adrenal incidentalomas (particularly when they occur in patients with known extra-adrenal malignancies). There are a variety of adrenal tissue characteristics with potential for exploitation but which are not currently in clinical use, and which may, nevertheless, have potential as imaging agents. These include: (a) inhibitors of adrenal cortical steroid hormone synthesis enzymes (e.g. radiolabelled analogues of metyrapone); (b) radiolabelled lipoproteins which bind to adrenocortical LDL receptors; (c) inhibitors of catecholamine biosynthesis enzymes (e.g. radiolabelled analogues of tyrosine and related amino acids); (d) cell surface receptors for various peptides and hormones which may be over-expressed on adrenal cortical or adrenal medullary tumours (e.g. radiolabelled analogues of ACTH on adrenocortical cells of zona fasciculata or zona glomerulosa origin, neurotransmitter/hormone message peptides binding to cell surface receptors such as bombesin, vasoactive intestinal polypeptide, cholecystokinin and opiate peptides); (e) the adrenal cortex can also synthesise cholesterol ab initio from acetate, and preliminary studies with (11)C-acetate positron emission tomography have shown interesting results.

scholarly journals Inducible Polarized Secretion of Exosomes in T and B Lymphocytes

2020 ◽  
Vol 21 (7) ◽  
pp. 2631 ◽  
Author(s):  
Victor Calvo ◽  
Manuel Izquierdo
Keyword(s):  
Immune System ◽  
T Lymphocytes ◽  
Cell Surface ◽  
B Lymphocytes ◽  
Synaptic Cleft ◽  
T And B Lymphocytes ◽  
Cell Surface Receptors ◽  
Microtubule Organization ◽  
Cell Receptors ◽  
Surface Receptors

Exosomes are extracellular vesicles (EV) of endosomal origin (multivesicular bodies, MVB) constitutively released by many different eukaryotic cells by fusion of MVB to the plasma membrane. However, inducible exosome secretion controlled by cell surface receptors is restricted to very few cell types and a limited number of cell surface receptors. Among these, exosome secretion is induced in T lymphocytes and B lymphocytes when stimulated at the immune synapse (IS) via T-cell receptors (TCR) and B-cell receptors (BCR), respectively. IS formation by T and B lymphocytes constitutes a crucial event involved in antigen-specific, cellular, and humoral immune responses. Upon IS formation by T and B lymphocytes with antigen-presenting cells (APC), the convergence of MVB towards the microtubule organization center (MTOC), and MTOC polarization to the IS, are involved in polarized exosome secretion at the synaptic cleft. This specialized mechanism provides the immune system with a finely-tuned strategy to increase the specificity and efficiency of crucial secretory effector functions of B and T lymphocytes. As inducible exosome secretion by antigen-receptors is a critical and unique feature of the immune system this review considers the study of the traffic events leading to polarized exosome secretion at the IS and some of their biological consequences.

scholarly journals FGF1 Fusions with the Fc Fragment of IgG1 for the Assembly of GFPpolygons-Mediated Multivalent Complexes Recognizing FGFRs

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1088
Author(s):  
Marta Poźniak ◽  
Weronika Zarzycka ◽  
Natalia Porębska ◽  
Agata Knapik ◽  
Paulina Marczakiewicz-Perera ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Fate ◽  
Biologically Active ◽  
Fine Tuning ◽  
Cell Surface Receptors ◽  
Fc Fragment ◽  
Surface Receptors ◽  
Cellular Processes ◽  
Novel Approach ◽  
Trigger Receptor

FGFRs are cell surface receptors that, when activated by specific FGFs ligands, transmit signals through the plasma membrane, regulating key cellular processes such as differentiation, division, motility, metabolism and death. We have recently shown that the modulation of the spatial distribution of FGFR1 at the cell surface constitutes an additional mechanism for fine-tuning cellular signaling. Depending on the multivalent, engineered ligand used, the clustering of FGFR1 into diverse supramolecular complexes enhances the efficiency and modifies the mechanism of receptor endocytosis, alters FGFR1 lifetime and modifies receptor signaling, ultimately determining cell fate. Here, we present a novel approach to generate multivalent FGFR1 ligands. We functionalized FGF1 for controlled oligomerization by developing N- and C-terminal fusions of FGF1 with the Fc fragment of human IgG1 (FGF1-Fc and Fc-FGF1). As oligomerization scaffolds, we employed GFPpolygons, engineered GFP variants capable of well-ordered multivalent display, fused to protein G to ensure binding of Fc fragment. The presented strategy allows efficient assembly of oligomeric FGFR1 ligands with up to twelve receptor binding sites. We show that multivalent FGFR1 ligands are biologically active and trigger receptor clustering on the cell surface. Importantly, the approach described in this study can be easily adapted to oligomerize alternative growth factors to control the activity of other cell surface receptors.

scholarly journals Mutual Potentiation of Plant Immunity by Cell-surface and Intracellular Receptors

2020 ◽  
Author(s):  
Bruno Pok Man Ngou ◽  
Hee-Kyung Ahn ◽  
Pingtao Ding ◽  
Jonathan DG Jones
Keyword(s):  
Immune System ◽  
Cell Surface ◽  
Pseudomonas Syringae ◽  
Plant Immunity ◽  
Cell Surface Receptor ◽  
Hypersensitive Cell Death ◽  
Surface Receptors ◽  
Intracellular Receptor ◽  
Surface Receptor ◽  
Immune Pathways

The plant immune system involves cell-surface receptors that detect intercellular pathogen-derived molecules, and intracellular receptors that activate immunity upon detection of pathogen-secreted effectors that act inside the plant cell. Surface receptor-mediated immunity has been extensively studied but in authentic interactions between plants and microbial pathogens, its presence impedes study of intracellular receptor-mediated immunity alone. How these two immune pathways interact is poorly understood. Here, we reveal mutual potentiation between these two recognition-dependent defense pathways. Recognition by surface receptors activates multiple protein kinases and NADPH oxidases, whereas intracellular receptors primarily elevate abundance of these proteins. Reciprocally, the intracellular receptor-dependent hypersensitive cell death response is strongly enhanced by activation of surface receptors. Activation of either immune system alone is insufficient to provide effective resistance against Pseudomonas syringae. Thus, immune pathways activated by cell-surface and intracellular receptors mutually potentiate to activate strong defense that thwarts pathogens. By studying the activation of intracellular receptors in the absence of surface receptor-mediated immunity, we have dissected the relationship between the two distinct immune systems. These findings reshape our understanding of plant immunity and have broad implications for crop improvement.

scholarly journals Recognition of human urine α-N-acetylglucosaminidase by rat hepatocytes. Involvement of receptors specific for galactose, mannose 6-phosphate and mannose

1979 ◽  
Vol 180 (2) ◽  
pp. 413-419 ◽  
Author(s):  
K Ullrich ◽  
R Basner ◽  
V Gieselmann ◽  
K Von Figura
Keyword(s):  
Cell Surface ◽  
Human Urine ◽  
Rat Hepatocytes ◽  
Cell Surface Receptor ◽  
Cell Surface Receptors ◽  
Minor Role ◽  
Isolated Rat Hepatocytes ◽  
Surface Receptors ◽  
Terminal Galactose ◽  
Mannose 6 Phosphate

Adsorptive endocytosis of alpha-N-acetylglucosaminidase from human urine by isolated rat hepatocytes is inhibited by glycoproteins, polysaccharides and sugars that are known to bind to cell-surface receptors specific for either terminal galactose/N-acetylgalactosamine residues, terminal mannose residues or mannose 6-phosphate residues. Recognition of alpha-N-acetylglucosaminidase by a cell-surface receptor specific for terminal galactose/N-acetylgalactosamine residues is supported by the observations (a) that neuraminidase pretreatment of the enzyme enhances endocytosis, (b) that beta-galactosidase treatment decreases endocytosis and (c) that neuraminidase pretreatment of hepatocytes decreases alpha-N-acetylglucosaminidase endocytosis. Recognition of alpha-N-acetylglucosaminidase via receptors recognizing mannose 6-phosphate residues is lost after treatment of the enzyme with alkaline phosphatase and endoglucosaminidase H. The effect of endoglucosaminidase H supports the view that the mannose 6-phosphate residues reside in N-glycosidically linked oligosaccharide side chains of the high-mannose type. The weak inhibition of endocytosis produced by compounds known to interact with cell-surface receptors specific for mannose residues suggests that this recognition system plays only a minor role in the endocytosis of lysosomal alpha-N-acetylglucosaminidase by hepatocytes.

scholarly journals SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators

2021 ◽  
Vol 49 (17) ◽  
pp. 9633-9647
Author(s):  
Xiaojun Ma ◽  
Ashwin Somasundaram ◽  
Zengbiao Qi ◽  
Douglas J Hartman ◽  
Harinder Singh ◽  
...  
Keyword(s):  
Cell Surface ◽  
Single Cell ◽  
Transcriptional Regulators ◽  
Cell Types ◽  
Receptor Expression ◽  
Cell Surface Receptor ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
Surface Receptor ◽  
Context Specific

Abstract The identity and functions of specialized cell types are dependent on the complex interplay between signaling and transcriptional networks. Recently single-cell technologies have been developed that enable simultaneous quantitative analysis of cell-surface receptor expression with transcriptional states. To date, these datasets have not been used to systematically develop cell-context-specific maps of the interface between signaling and transcriptional regulators orchestrating cellular identity and function. We present SPaRTAN (Single-cell Proteomic and RNA based Transcription factor Activity Network), a computational method to link cell-surface receptors to transcription factors (TFs) by exploiting cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) datasets with cis-regulatory information. SPaRTAN is applied to immune cell types in the blood to predict the coupling of signaling receptors with cell context-specific TFs. Selected predictions are validated by prior knowledge and flow cytometry analyses. SPaRTAN is then used to predict the signaling coupled TF states of tumor infiltrating CD8+ T cells in malignant peritoneal and pleural mesotheliomas. SPaRTAN enhances the utility of CITE-seq datasets to uncover TF and cell-surface receptor relationships in diverse cellular states.

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