scholarly journals Lack of evidence for a role of anthrax toxin receptors as surface receptors for collagen VI and for its cleaved off C5 domain (endotrophin)

2021 ◽  
Author(s):  
Matthias Przyklenk ◽  
Stefanie Elisabeth Heumueller ◽  
Steffen Luetke ◽  
Gerhard Sengle ◽  
Manuel Koch ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Physiological Role ◽  
Potential Interaction ◽  
Anthrax Toxin ◽  
Close Relative ◽  
Collagen Vi ◽  
Surface Receptors ◽  
Surface Receptor ◽  
Toxin Receptor

The widely expressed microfibril-forming collagen VI is subject to proteolytic cleavage and it has been proposed that the cleaved off C-terminal Kunitz domain (C5) of the α3 chain is an adipokine important for tumor progression and fibrosis. Under the name endotrophin the C5 fragment has also been shown to be a potent biomarker for fibro-inflammatory diseases. However, the biochemical mechanisms behind endotrophin activity have not been investigated. In earlier studies, the anthrax toxin receptor 1 was found to bind to C5, but this potential interaction has not been further studied. Given the proposed physiological role of endotrophin we aimed to determine how the endotrophin signal is transmitted to the recipient cells. Surprisingly, we could not detect any interaction between endotrophin and anthrax toxin receptor 1 or its close relative, anthrax toxin receptor 2. Moreover, we could not detect binding of fully assembled collagen VI to either anthrax toxin receptor. We also performed similar experiments with the collagen VI surface receptor NG2 (CSPG4). We could confirm that NG2 is a collagen VI receptor that binds to assembled collagen VI, but not to the cleaved C5/endotrophin. A cellular receptor for C5/endotrophin therefore still remains elusive.

scholarly journals Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process

2003 ◽  
Vol 160 (3) ◽  
pp. 321-328 ◽  
Author(s):  
Laurence Abrami ◽  
Shihui Liu ◽  
Pierre Cosson ◽  
Stephen H. Leppla ◽  
F. Gisou van der Goot
Keyword(s):  
Lipid Rafts ◽  
Protective Antigen ◽  
Lethal Factor ◽  
Physiological Role ◽  
Membrane Lipid ◽  
Anthrax Toxin ◽  
Cell Surface Receptor ◽  
Surface Receptor ◽  
Toxin Receptor ◽  
Major Route

The protective antigen (PA) of the anthrax toxin binds to a cell surface receptor and thereby allows lethal factor (LF) to be taken up and exert its toxic effect in the cytoplasm. Here, we report that clustering of the anthrax toxin receptor (ATR) with heptameric PA or with an antibody sandwich causes its association to specialized cholesterol and glycosphingolipid-rich microdomains of the plasma membrane (lipid rafts). We find that although endocytosis of ATR is slow, clustering it into rafts either via PA heptamerization or using an antibody sandwich is necessary and sufficient to trigger efficient internalization and allow delivery of LF to the cytoplasm. Importantly, altering raft integrity using drugs prevented LF delivery and cleavage of cytosolic MAPK kinases, suggesting that lipid rafts could be therapeutic targets for drugs against anthrax. Moreover, we show that internalization of PA is dynamin and Eps15 dependent, indicating that the clathrin-dependent pathway is the major route of anthrax toxin entry into the cell. The present work illustrates that although the physiological role of the ATR is unknown, its trafficking properties, i.e., slow endocytosis as a monomer and rapid clathrin-mediated uptake on clustering, make it an ideal anthrax toxin receptor.

scholarly journals The Role of Autophagy in Immunity and Autoimmune Diseases / Uloga Autofagije U Imunskom Odgovoru I Autoimunskim Bolestima

2014 ◽  
Vol 15 (4) ◽  
pp. 223-229
Author(s):  
Bojana Simovic Markovic ◽  
Ljubica Vucicevic ◽  
Sanja Bojic ◽  
Vladislav Volarevic
Keyword(s):  
Autoimmune Diseases ◽  
Potential Role ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Physiological Role ◽  
Immune Functions ◽  
Complex Relationships ◽  
Cellular Components ◽  
Chaperone Mediated Autophagy

ABSTRACT Autophagy is a catabolic mechanism in the cell that involves the degradation of unnecessary or dysfunctional cellular components by the lysosomal machinery. Recent studies have indicated that autophagy is a source of autoantigens, thus highlighting its potential role in the pathogenesis of autoimmunity. There are at least three different forms of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). The physiological role of autophagy is to maintain cellular homeostasis by removing long-lived, damaged proteins and dysfunctional organelles and by providing energy. Aberrant autophagy may contribute to chronic inflammatory diseases and autoimmune diseases. An understanding of the complex relationships between autophagy and autophagy-related genes in each autoimmune disease creates the possibility of developing more specific and effective therapeutic strategies. Given the importance of autophagy in immune functions, this review article summarises current knowledge about the role of autophagy in the pathogenesis of autoimmune diseases.

scholarly journals Antithrombin and Its Role in Host Defense and Inflammation

2021 ◽  
Vol 22 (8) ◽  
pp. 4283
Author(s):  
Christine Schlömmer ◽  
Anna Brandtner ◽  
Mirjam Bachler
Keyword(s):  
Cell Walls ◽  
Inflammatory Diseases ◽  
Antibacterial Properties ◽  
Coagulation System ◽  
Peptide Fragments ◽  
Inflammatory Signaling ◽  
Surface Receptors ◽  
Inflammatory Conditions ◽  
Randomized Control

Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic heparin. However, AT levels drop in systemic inflammatory diseases. The reason for this decline is consumption by the coagulation system but also by immunological processes. Aside from the primarily known anticoagulant effects, AT elicits distinct anti-inflammatory signaling responses. It binds to structures of the glycocalyx (syndecan-4) and further modulates the inflammatory response of endothelial cells and leukocytes by interacting with surface receptors. Additionally, AT exerts direct antimicrobial effects: depending on AT glycosylation it can bind to and perforate bacterial cell walls. Peptide fragments derived from proteolytic degradation of AT exert antibacterial properties. Despite these promising characteristics, therapeutic supplementation in inflammatory conditions has not proven to be effective in randomized control trials. Nevertheless, new insights provided by subgroup analyses and retrospective trials suggest that a recommendation be made to identify the patient population that would benefit most from AT substitution. Recent experiment findings place the role of various AT isoforms in the spotlight. This review provides an overview of new insights into a supposedly well-known molecule.

scholarly journals Physiological Role of Bile Acids Modified by the Gut Microbiome

2021 ◽  
Vol 10 (1) ◽  
pp. 68
Author(s):  
Yoshimitsu Kiriyama ◽  
Hiromi Nochi
Keyword(s):  
Cell Surface ◽  
Bile Acids ◽  
Terminal Ileum ◽  
Gut Microbiome ◽  
Physiological Role ◽  
Systemic Circulation ◽  
Nervous Systems ◽  
Physiological Regulation ◽  
Surface Receptors

Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver and then released into the intestine via the gallbladder. After the deconjugation of glycine or taurine by the gut microbiome, primary BAs are converted into secondary BAs by the gut microbiome through modifications such as dehydroxylation, oxidation, and epimerization. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine. Thus, unconjugated primary Bas, as well as conjugated and unconjugated secondary BAs, have been modified by the gut microbiome. Some of the BAs reabsorbed from the intestine spill into the systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues, whereas some of the BAs are not reabsorbed and bind to receptors in the terminal ileum. BAs play crucial roles in the physiological regulation of various tissues. Furthermore, various factors, such as diet, age, and antibiotics influence BA composition. Here, we review recent findings regarding the physiological roles of BAs modified by the gut microbiome in the metabolic, immune, and nervous systems.

Attachment of human vascular smooth muscles cells to intact microfibrillar assemblies of collagen VI and fibrillin

1992 ◽  
Vol 103 (2) ◽  
pp. 445-451 ◽  
Author(s):  
C.M. Kielty ◽  
S.P. Whittaker ◽  
M.E. Grant ◽  
C.A. Shuttleworth
Keyword(s):  
Smooth Muscle ◽  
Cell Adhesion ◽  
Smooth Muscle Cells ◽  
Cell Attachment ◽  
Smooth Muscles ◽  
Physiological Role ◽  
Muscle Cells ◽  
Collagen Vi ◽  
Surface Receptors ◽  
Adhesion Activity

Human vascular smooth muscle cells have been used to assess the implied role of connective tissue microfibrils as cellular ligands. Preparations of intact high-M(r) microfibrillar assemblies of collagen VI and of fibrillin, respectively, were isolated from foetal bovine skin and used as ligands in cell attachment and spreading assays. Intact collagen VI microfibrils were capable of mediating cell attachment and partial spreading. Cell attachment assays using ligands composed of defined collagen VI fragments generated by pepsin or bacterial collagenase digestions demonstrated that both the triple-helical and non-collagenous domains of collagen VI had cell adhesion activity, although at reduced levels relative to intact microfibrils. Fibronectin was identified as a modulator of intact collagen VI microfibril-mediated cell attachment. These observations are indicative of complex multiple interactions between collagen VI microfibrils and smooth muscle cells. Purified fibrillin-containing microfibrils were also shown to support smooth muscle cell adhesion. Both pepsin-resistant and pepsin-sensitive domains of fibrillin exhibited some cell attachment activity, but at reduced levels relative to the intact fibrillin microfibrils. These data provide the first direct evidence of a physiological role for intact microfibrillar assemblies in cell-matrix interactions, and the involvement of integrin cell surface receptors containing the beta 1 subunit.

scholarly journals The Potential Interplay of Adipokines with Toll-Like Receptors in the Development of Hepatocellular Carcinoma

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Shen-Nien Wang ◽  
Sen-Te Wang ◽  
King Teh Lee
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chronic Inflammation ◽  
Metabolic Diseases ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Epidemiological Data ◽  
Potential Interaction ◽  
Potential Contribution ◽  
Toll Like Receptors

Toll-like receptors (TLRs) are not only crucial to the initiation of the immune system, but also play a key role in several human inflammatory diseases. Hepatocellular carcinoma (HCC) is among those human cancers, which arise from sites of chronic inflammation. Therefore, a number of studies have explored the potential contribution of TLRs to HCC occurrence, which is initiated by exposure to chronic hepatic inflammation of different etiologies (including ethanol, and chronic B and C viral infections). Recent epidemiological data have shown the association of obesity and HCC development. Given the fact that adipose tissues can produce a variety of inflammation-related adipokines, obesity has been characterized as a state of chronic inflammation. Adipokines are therefore considered as important mediators linking inflammation to several metabolic diseases, including cancers. More recently, many experts have also shown the bridging role of TLRs between inflammation and metabolism. Hopefully, to retrieve the potential interaction between TLRs and adipokines in carcinogenesis of HCC will shed a new light on the therapeutic alternative for HCC. In this paper, the authors first review the respective roles of TLRs and adipokines, discuss their mutual interaction in chronic inflammation, and finally anticipate further investigations of this interaction in HCC development.

scholarly journals Control of cellular motility by neuropilin-mediated physical interactions

2014 ◽  
Vol 5 (2) ◽  
pp. 157-166 ◽  
Author(s):  
Xiaobo Li ◽  
Matthew W. Parker ◽  
Craig W. Vander Kooi
Keyword(s):  
Physiological Role ◽  
Cellular Adhesion ◽  
Cellular Migration ◽  
Cellular Motility ◽  
Tumor Cell Migration ◽  
Surface Receptors ◽  
Multistep Process ◽  
Physical Interactions ◽  
Adhesive Interactions

AbstractThe neuropilin (Nrp) family consists of multifunctional cell surface receptors with critical roles in a number of different cell and tissue types. A core aspect of Nrp function is in ligand-dependent cellular migration, where it controls the multistep process of cellular motility through integration of ligand binding and receptor signaling. At a molecular level, the role of Nrp in migration is intimately connected to the control of adhesive interactions and cytoskeletal reorganization. Here, we review the physiological role of Nrp in cellular adhesion and motility in the cardiovascular and nervous systems. We also discuss the emerging pathological role of Nrp in tumor cell migration and metastasis, providing motivation for continued efforts toward developing Nrp inhibitors.

Altered role of microtubules in asialoglycoprotein trafficking in developing liver

1990 ◽  
Vol 258 (1) ◽  
pp. G129-G137
Author(s):  
S. S. Kaufman ◽  
P. L. Blain ◽  
J. H. Park ◽  
D. J. Tuma
Keyword(s):  
Protein Trafficking ◽  
Rat Hepatocytes ◽  
Neonatal Rat ◽  
Surface Receptors ◽  
Surface Receptor ◽  
Neonatal Hepatocytes ◽  
Adult Rate ◽  
Reduced Surface ◽  
Adult Cells

Efficient receptor-mediated endocytosis of asialoglycoprotein by mature liver requires participation of microtubules that convey newly internalized ligand to lysosomes for degradation and receptor back to plasma membrane to continue endocytosis. To ascertain whether microtubular participation in asialoglycoprotein endocytosis is altered during development, we compared endocytosis of 125I-labeled asialoorosomucoid (ASOR) in neonatal rat hepatocytes to that in adult cells, with and without microtubular disruption by colchicine. Control experiments demonstrated that 125I-ASOR degradation in neonatal hepatocytes occurred at 70% of the adult rate during continuous endocytosis, although neonatal surface receptors were only approximately 40% as numerous. Colchicine disruption of microtubules reduced 125I-ASOR degradation and steady-state intracellular ASOR more in adults during continuous endocytosis. Degradation of 125I-ASOR prebound to surface receptors was equally impaired by colchicine in the two groups. Continuous ASOR endocytosis by colchicine-treated adult hepatocytes progressively depleted their surface receptors but minimally in neonates. Unlike colchicine, the protonophore monensin markedly impaired receptor recycling as well as postinternalization ligand trafficking in both neonates and adults. Thus these experiments demonstrate that asialoglycoprotein processing proceeds as efficiently in neonatal as in adult hepatocytes despite a reduced surface receptor population. Microtubules are required to maintain receptors on cell surface as well as for postinternalization trafficking in adult cells. During development, only the latter process substantially requires microtubules, indicating that microtubular participation in protein trafficking is selectively, not uniformly, diminished at this time in life.

An overview of high-mobility group box 1, a potent pro-inflammatory cytokine in asthma

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Farzaneh Kianian ◽  
Mehri Kadkhodaee ◽  
Hamid Reza Sadeghipour ◽  
Seyed Morteza Karimian ◽  
Behjat Seifi
Keyword(s):  
Inflammatory Cytokine ◽  
Inflammatory Diseases ◽  
High Mobility ◽  
Chronic Respiratory Disease ◽  
High Mobility Group ◽  
High Morbidity ◽  
Surface Receptors ◽  
Nucleosome Formation ◽  
Central Characteristic

AbstractHigh-mobility group box 1 (HMGB1), also called amphoterin, HMG1 and p30, is a highly conserved protein between different species that has various functions in nucleus such as stabilization of nucleosome formation, facilitation of deoxyribonucleic acid (DNA) bending and increasing the DNA transcription, replication and repair. It has also been indicated that HMGB1 acts as a potent pro-inflammatory cytokine with increasing concentrations in acute and chronic inflammatory diseases. Asthma is a common chronic respiratory disease associated with high morbidity and mortality rates. One central characteristic in its pathogenesis is airway inflammation. Considering the inflammatory role of HMGB1 and importance of inflammation in asthma pathogenesis, a better understanding of this protein is vital. This review describes the structure, cell surface receptors, signaling pathways and intracellular and extracellular functions of HMGB1, but also focuses on its inflammatory role in asthma. Moreover, this manuscript reviews experimental and clinical studies that investigated the pathologic role of HMGB1.

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