The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Klaas Bouwmeester - One of the best experts on this subject based on the ideXlab platform.
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l type Lectin Receptor kinases in nicotiana benthamiana and tomato and their role in phytophthora resistance
Journal of Experimental Botany, 2015Co-Authors: Yan Wang, Klaas Bouwmeester, Francine Govers, R WeideAbstract:Membrane-bound Receptors play crucial roles as sentinels of plant immunity against a large variety of invading microbes. One class of Receptors known to be involved in self/non-self-surveillance and plant resistance comprises the L-type Lectin Receptor kinases (LecRKs). Previously, we reported that several Arabidopsis LecRKs play a role in resistance to Phytophthora pathogens. In this study, we determined whether homologues of these LecRKs from the Solanaceous plants Nicotiana benthamiana and tomato (Solanum lycopersicum) play similar roles in defence against Phytophthora. In genome-wide screenings, a total of 38 (Nb)LecRKs were identified in N. benthamiana and 22 (Sl)LecRKs in tomato, each consisting of both a Lectin and a kinase domain. Phylogenetic analysis revealed that, in contrast to Arabidopsis, which has a LecRK family comprising nine clades, Solanaceous species have just five of these nine clades (i.e. IV, VI, VII, VIII, and IX), plus four additional clades that lack Arabidopsis homologues. Several of the Solanaceous LecRKs were selected for functional analysis using virus-induced gene silencing. Infection assays with Phytophthora capsici and Phytophthora infestans on LecRK-silenced plants revealed that N. benthamiana and tomato homologues in clade IX play a role in Phytophthora resistance similar to the two Arabidopsis LecRKs in this clade, suggesting conserved functions of clade IX LecRKs across different plant families. This study provides a first insight into the diversity of Solanaceous LecRKs and their role in plant immunity, and shows the potential of LecRKs for Phytophthora resistance breeding.
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the arabidopsis Lectin Receptor kinase lecrk i 9 enhances resistance to phytophthora infestans in solanaceous plants
Plant Biotechnology Journal, 2014Co-Authors: Klaas Bouwmeester, Rosario Blancoportales, Wei Song, R Weide, Edwin A G Van Der Vossen, Francine GoversAbstract:Late blight caused by the plant pathogenic oomycete Phytophthora infestans is known as one of the most destructive potato diseases. Plant breeders tend to employ NB-LRR-based resistance for introducing genetically controlled late blight resistance in their breeding lines. However, P. infestans is able to rapidly escape this type of resistance, and hence, NB-LRR-based resistance in potato cultivars is often not durable. Previously, we identified a novel type of Phytophthora resistance in Arabidopsis. This resistance is mediated by the cell surface Receptor LecRK-I.9, which belongs to the family of L-type Lectin Receptor kinases. In this study, we report that expression of the Arabidopsis LecRK-I.9 gene in potato and Nicotiana benthamiana results in significantly enhanced late blight resistance. Transcriptional profiling showed strong reduction in salicylic acid (SA)-mediated defence gene expression in LecRK-I.9 transgenic potato lines (TPLs). In contrast, transcripts of two protease inhibitor genes accumulated to extreme high levels, suggesting that LecRK-I.9-mediated late blight resistance is relying on a defence response that includes activation of protease inhibitors. These results demonstrate that the functionality of LecRK-I.9 in Phytophthora resistance is maintained after interfamily transfer to potato and N. benthamiana and suggest that this novel type of LecRK-based resistance can be exploited in breeding strategies to improve durable late blight resistance in Solanaceous crops.
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the Lectin Receptor kinase lecrk i 9 is a novel phytophthora resistance component and a potential host target for a rxlr effector
PLOS Pathogens, 2011Co-Authors: Klaas Bouwmeester, Anne Gouget, Hervé Canut, R Weide, Mara De Sain, Sofieke Klamer, Francine GoversAbstract:In plants, an active defense against biotrophic pathogens is dependent on a functional continuum between the cell wall (CW) and the plasma membrane (PM). It is thus anticipated that proteins maintaining this continuum also function in defense. The legume-like Lectin Receptor kinase LecRK-I.9 is a putative mediator of CW-PM adhesions in Arabidopsis and is known to bind in vitro to the Phytophthora infestans RXLR-dEER effector IPI-O via a RGD cell attachment motif present in IPI-O. Here we show that LecRK-I.9 is associated with the plasma membrane, and that two T-DNA insertions lines deficient in LecRK-I.9 (lecrk-I.9) have a ‘gain-of-susceptibility’ phenotype specifically towards the oomycete Phytophthora brassicae. Accordingly, overexpression of LecRK-I.9 leads to enhanced resistance to P. brassicae. A similar ‘gain-of-susceptibility’ phenotype was observed in transgenic Arabidopsis lines expressing ipiO (35S-ipiO1). This phenocopy behavior was also observed with respect to other defense-related functions; lecrk-I.9 and 35S-ipiO1 were both disturbed in pathogen- and MAMP-triggered callose deposition. By site-directed mutagenesis, we demonstrated that the RGD cell attachment motif in IPI-O is not only essential for disrupting the CW-PM adhesions, but also for disease suppression. These results suggest that destabilizing the CW-PM continuum is one of the tactics used by Phytophthora to promote infection. As countermeasure the host may want to strengthen CW-PM adhesions and the novel Phytophthora resistance component LecRK-I.9 seems to function in this process.
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Arabidopsis L-type Lectin Receptor kinases: phylogeny, classification, and expression profiles
Journal of experimental botany, 2009Co-Authors: Klaas Bouwmeester, Francine GoversAbstract:In plants, Lectin Receptor kinases are considered to play crucial roles during development and in the adaptive response to various stimuli. Arabidopsis Lectin Receptor kinases can be divided into three type-classes based on sequence similarity of their extracellular Lectin motifs. The current study focuses on the legume-like Lectin Receptor kinases (LecRKs), which are regarded as ideal candidates for monitoring cell wall integrity and are possibly functional in adaptive responses. An inventory of the Arabidopsis LecRK gene family is presented here. It consists of 45 members including three that were recently identified; two encode N-terminal truncated variants one of which has two in tandem kinase domains. Phylogenetic trees derived from full-length amino acid sequence alignments were highly concordant to phylograms that were purely based on Lectin motifs or kinase domains. The phylograms allowed reclassification of the LecRK genes and hence a new proposal for gene nomenclature was suggested. In addition, a comprehensive expression analysis was executed by exploring public repositories. This revealed that several LecRK genes are differentially expressed during plant growth and development. Moreover, multiple LecRKs appear to be induced upon treatment with elicitors and pathogen infection. Variation in gene expression was also analysed in seedlings of diverse Arabidopsis accessions. Taken together, this study provides a genome-wide overview of the LecRK gene family and an up-to-date classification using a novel and systematic gene nomenclature.
Christoph Rademacher - One of the best experts on this subject based on the ideXlab platform.
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high affinity sugar ligands of c type Lectin Receptor langerin
Biochimica et Biophysica Acta, 2018Co-Authors: Tetsuya Hirayama, Masahiro Nagata, Hendra S Ismanto, Bernd Lepenies, Jonas Aretz, Yasuhiko Kizuka, Reiko Fujinawa, Yoshiki Yamaguchi, Christoph RademacherAbstract:Abstract Background Langerin, a C-type Lectin Receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti-inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application. Methods We performed binding analysis between purified long and short forms of langerin and a series of KS disaccharide components. We also chemically synthesized oligomeric derivatives of L4 to develop a new high-affinity ligand of langerin. Results We show that the binding critically requires the 6-sulfation of Gal and that the long form of langerin displays higher affinity than the short form. The synthesized trimeric (also designated as triangle or Tri) and polymeric (pendant) L4 derivatives displayed over 1000-fold higher affinity toward langerin than monomeric L4. The pendant L4, but not the L4 monomer, was found to effectively transduce langerin signaling in a model cell system. Conclusions L4 is a specific ligand for langerin. Oligomerization of L4 unit increased the affinity toward langerin. General significance These results suggest that oligomeric L4 derivatives will be useful for clarifying the langerin functions and for the development of new glycan-based anti-inflammatory drugs.
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calcium independent activation of an allosteric network in langerin by heparin oligosaccharides
ChemBioChem, 2017Co-Authors: Jonas Hanske, Robert Wawrzinek, Andreas Geissner, Katrin Sellrie, Eike-christian Wamhoff, Henrik Schmidt, Peter H. Seeberger, Christoph RademacherAbstract:The C-type Lectin Receptor Langerin is a glycan-binding protein that serves as an uptake Receptor on Langerhans cells and is essential for the formation of Birbeck granules. Whereas most Langerin ligands are recognized by a canonical Ca2+-dependent binding site, heparins have been proposed to make additional contacts to a secondary, Ca2+-independent site. Glycan array screening and biomolecular NMR spectroscopy were employed to investigate the molecular mechanism of these interactions. We observed that binding of heparin hexasaccharides to a secondary site did not require the presence of Ca2+ and activated a previously identified intradomain allosteric network of Langerin (thus far only associated with Ca2+ affinity and release). We propose a communication hub between these two binding sites, which sheds new light on modulatory functions of Langerin–heparin interactions.
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intradomain allosteric network modulates calcium affinity of the c type Lectin Receptor langerin
Journal of the American Chemical Society, 2016Co-Authors: Jonas Hanske, Stevan Aleksic, Martin Ballaschk, Marcel Jurk, Elena Shanina, Monika Beerbaum, Peter Schmieder, Bettina G Keller, Christoph RademacherAbstract:Antigen uptake and processing by innate immune cells is crucial to initiate the immune response. Therein, the endocytic C-type Lectin Receptors serve as pattern recognition Receptors, detecting pathogens by their glycan structures. Herein, we studied the carbohydrate recognition domain of Langerin, a C-type Lectin Receptor involved in the host defense against viruses such as HIV and influenza as well as bacteria and fungi. Using a combination of nuclear magnetic resonance and molecular dynamics simulations, we unraveled the molecular determinants underlying cargo capture and release encoded in the Receptor architecture. Our findings revealed Receptor dynamics over several time scales associated with binding and release of the essential cofactor Ca2+ controlled by the coupled motions of two loops. Applying mutual information theory and site-directed mutagenesis, we identified an allosteric intradomain network that modulates the Ca2+ affinity depending on the pH, thereby promoting fast ligand release.
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computational and experimental prediction of human c type Lectin Receptor druggability
Frontiers in Immunology, 2014Co-Authors: Jonas Aretz, Eike-christian Wamhoff, Jonas Hanske, Dario Heymann, Christoph RademacherAbstract:Mammalian C-type Lectin Receptors (CTLRS) are involved in many aspects of immune cell regulation such as pathogen recognition, clearance of apoptotic bodies, and lymphocyte homing. Despite a great interest in modulating CTLR recognition of carbohydrates, the number of specific molecular probes is limited. To this end, we predicted the druggability of a panel of 22 CTLRs using DoGSiteScorer. The computed druggability scores of most structures were low, characterizing this family as either challenging or even undruggable.To further explore these findings, we employed a fluorine-based nuclear magnetic resonance screening of fragment mixtures against DC-SIGN, a Receptor of pharmacological interest. To our surprise, we found many fragment hits associated with the carbohydrate recognition site (hit rateD 13.5%). A surface plasmon resonance-based follow-up assay confirmed 18 of these fragments (47%) and equilibrium dissociation constants were determined. Encouraged by these findings we expanded our experimental druggability prediction to Langerin and MCL and found medium to high hit rates as well, being 15.7 and 10.0%, respectively. Our results highlight limitations of current in silico approaches to druggability assessment, in particular, with regard to carbohydrate-binding proteins. In sum, our data indicate that small molecule ligands for a larger panel of CTLRs can be developed.
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computational and experimental prediction of human c type Lectin Receptor druggability
Frontiers in Immunology, 2014Co-Authors: Jonas Aretz, Eike-christian Wamhoff, Jonas Hanske, Dario Heymann, Christoph RademacherAbstract:Mammalian C-type Lectin Receptors (CTLRS) are involved in many aspects of immune cell regulation such as pathogen recognition, clearance of apoptotic bodies, and lymphocyte homing. Despite a great interest in modulating CTLR recognition of carbohydrates, the number of specific molecular probes is limited. To this end, we predicted the druggability of a panel of 22 CTLRs using DoGSiteScorer. The computed druggability scores of most structures were low, characterizing this family as either challenging or even undruggable.To further explore these findings, we employed a fluorine-based nuclear magnetic resonance screening of fragment mixtures against DC-SIGN, a Receptor of pharmacological interest. To our surprise, we found many fragment hits associated with the carbohydrate recognition site (hit rateD 13.5%). A surface plasmon resonance-based follow-up assay confirmed 18 of these fragments (47%) and equilibrium dissociation constants were determined. Encouraged by these findings we expanded our experimental druggability prediction to Langerin and MCL and found medium to high hit rates as well, being 15.7 and 10.0%, respectively. Our results highlight limitations of current in silico approaches to druggability assessment, in particular, with regard to carbohydrate-binding proteins. In sum, our data indicate that small molecule ligands for a larger panel of CTLRs can be developed.
Francine Govers - One of the best experts on this subject based on the ideXlab platform.
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The Arabidopsis thaliana Lectin Receptor kinase LecRK-I.9 is required for full resistance to Pseudomonas syringae and affects jasmonate signalling
Molecular Plant Pathology, 2017Co-Authors: Claudine Balagué, Francine Govers, Olivier Bouchez, Dominique Roby, Anne Gouget, Camille Souriac, Nathalie Haget, Stephanie Boutet-mercey, Hervé CanutAbstract:On microbial attack, plants can detect invaders and activate plant innate immunity. For the detection of pathogen molecules or cell wall damage, plants employ Receptors that trigger the activation of defence responses. Cell surface proteins that belong to large families of Lectin Receptor kinases are candidates to function as immune Receptors. Here, the function of LecRK-I.9 (At5g60300), a legume-type Lectin Receptor kinase involved in cell wall-plasma membrane contacts and in extracellular ATP (eATP) perception, was studied through biochemical, gene expression and reverse genetics approaches. In Arabidopsis thaliana, LecRK-I.9 expression is rapidly, highly and locally induced on inoculation with avirulent strains of Pseudomonas syringae pv. tomato (Pst). Two allelic lecrk-I.9 knock-out mutants showed decreased resistance to Pst. Conversely, over-expression of LecRK-I.9 led to increased resistance to Pst. The analysis of defence gene expression suggests an alteration of both the salicylic acid (SA) and jasmonic acid (JA) signalling pathways. In particular, LecRK-I.9 expression during plant-pathogen interaction was dependent on COI1 (CORONATINE INSENSITIVE 1) and JAR1 (JASMONATE RESISTANT 1) components, and JA-responsive transcription factors (TFs) showed altered levels of expression in plants over-expressing LecRK-I.9. A similar misregulation of these TFs was obtained by JA treatment. This study identified LecRK-I.9 as necessary for full resistance to Pst and demonstrated its involvement in the control of defence against pathogens through a regulation of JA signalling components. The role of LecRK-I.9 is discussed with regard to the potential molecular mechanisms linking JA signalling to cell wall damage and/or eATP perception.
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l type Lectin Receptor kinases in nicotiana benthamiana and tomato and their role in phytophthora resistance
Journal of Experimental Botany, 2015Co-Authors: Yan Wang, Klaas Bouwmeester, Francine Govers, R WeideAbstract:Membrane-bound Receptors play crucial roles as sentinels of plant immunity against a large variety of invading microbes. One class of Receptors known to be involved in self/non-self-surveillance and plant resistance comprises the L-type Lectin Receptor kinases (LecRKs). Previously, we reported that several Arabidopsis LecRKs play a role in resistance to Phytophthora pathogens. In this study, we determined whether homologues of these LecRKs from the Solanaceous plants Nicotiana benthamiana and tomato (Solanum lycopersicum) play similar roles in defence against Phytophthora. In genome-wide screenings, a total of 38 (Nb)LecRKs were identified in N. benthamiana and 22 (Sl)LecRKs in tomato, each consisting of both a Lectin and a kinase domain. Phylogenetic analysis revealed that, in contrast to Arabidopsis, which has a LecRK family comprising nine clades, Solanaceous species have just five of these nine clades (i.e. IV, VI, VII, VIII, and IX), plus four additional clades that lack Arabidopsis homologues. Several of the Solanaceous LecRKs were selected for functional analysis using virus-induced gene silencing. Infection assays with Phytophthora capsici and Phytophthora infestans on LecRK-silenced plants revealed that N. benthamiana and tomato homologues in clade IX play a role in Phytophthora resistance similar to the two Arabidopsis LecRKs in this clade, suggesting conserved functions of clade IX LecRKs across different plant families. This study provides a first insight into the diversity of Solanaceous LecRKs and their role in plant immunity, and shows the potential of LecRKs for Phytophthora resistance breeding.
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the arabidopsis Lectin Receptor kinase lecrk i 9 enhances resistance to phytophthora infestans in solanaceous plants
Plant Biotechnology Journal, 2014Co-Authors: Klaas Bouwmeester, Rosario Blancoportales, Wei Song, R Weide, Edwin A G Van Der Vossen, Francine GoversAbstract:Late blight caused by the plant pathogenic oomycete Phytophthora infestans is known as one of the most destructive potato diseases. Plant breeders tend to employ NB-LRR-based resistance for introducing genetically controlled late blight resistance in their breeding lines. However, P. infestans is able to rapidly escape this type of resistance, and hence, NB-LRR-based resistance in potato cultivars is often not durable. Previously, we identified a novel type of Phytophthora resistance in Arabidopsis. This resistance is mediated by the cell surface Receptor LecRK-I.9, which belongs to the family of L-type Lectin Receptor kinases. In this study, we report that expression of the Arabidopsis LecRK-I.9 gene in potato and Nicotiana benthamiana results in significantly enhanced late blight resistance. Transcriptional profiling showed strong reduction in salicylic acid (SA)-mediated defence gene expression in LecRK-I.9 transgenic potato lines (TPLs). In contrast, transcripts of two protease inhibitor genes accumulated to extreme high levels, suggesting that LecRK-I.9-mediated late blight resistance is relying on a defence response that includes activation of protease inhibitors. These results demonstrate that the functionality of LecRK-I.9 in Phytophthora resistance is maintained after interfamily transfer to potato and N. benthamiana and suggest that this novel type of LecRK-based resistance can be exploited in breeding strategies to improve durable late blight resistance in Solanaceous crops.
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the Lectin Receptor kinase lecrk i 9 is a novel phytophthora resistance component and a potential host target for a rxlr effector
PLOS Pathogens, 2011Co-Authors: Klaas Bouwmeester, Anne Gouget, Hervé Canut, R Weide, Mara De Sain, Sofieke Klamer, Francine GoversAbstract:In plants, an active defense against biotrophic pathogens is dependent on a functional continuum between the cell wall (CW) and the plasma membrane (PM). It is thus anticipated that proteins maintaining this continuum also function in defense. The legume-like Lectin Receptor kinase LecRK-I.9 is a putative mediator of CW-PM adhesions in Arabidopsis and is known to bind in vitro to the Phytophthora infestans RXLR-dEER effector IPI-O via a RGD cell attachment motif present in IPI-O. Here we show that LecRK-I.9 is associated with the plasma membrane, and that two T-DNA insertions lines deficient in LecRK-I.9 (lecrk-I.9) have a ‘gain-of-susceptibility’ phenotype specifically towards the oomycete Phytophthora brassicae. Accordingly, overexpression of LecRK-I.9 leads to enhanced resistance to P. brassicae. A similar ‘gain-of-susceptibility’ phenotype was observed in transgenic Arabidopsis lines expressing ipiO (35S-ipiO1). This phenocopy behavior was also observed with respect to other defense-related functions; lecrk-I.9 and 35S-ipiO1 were both disturbed in pathogen- and MAMP-triggered callose deposition. By site-directed mutagenesis, we demonstrated that the RGD cell attachment motif in IPI-O is not only essential for disrupting the CW-PM adhesions, but also for disease suppression. These results suggest that destabilizing the CW-PM continuum is one of the tactics used by Phytophthora to promote infection. As countermeasure the host may want to strengthen CW-PM adhesions and the novel Phytophthora resistance component LecRK-I.9 seems to function in this process.
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Arabidopsis L-type Lectin Receptor kinases: phylogeny, classification, and expression profiles
Journal of experimental botany, 2009Co-Authors: Klaas Bouwmeester, Francine GoversAbstract:In plants, Lectin Receptor kinases are considered to play crucial roles during development and in the adaptive response to various stimuli. Arabidopsis Lectin Receptor kinases can be divided into three type-classes based on sequence similarity of their extracellular Lectin motifs. The current study focuses on the legume-like Lectin Receptor kinases (LecRKs), which are regarded as ideal candidates for monitoring cell wall integrity and are possibly functional in adaptive responses. An inventory of the Arabidopsis LecRK gene family is presented here. It consists of 45 members including three that were recently identified; two encode N-terminal truncated variants one of which has two in tandem kinase domains. Phylogenetic trees derived from full-length amino acid sequence alignments were highly concordant to phylograms that were purely based on Lectin motifs or kinase domains. The phylograms allowed reclassification of the LecRK genes and hence a new proposal for gene nomenclature was suggested. In addition, a comprehensive expression analysis was executed by exploring public repositories. This revealed that several LecRK genes are differentially expressed during plant growth and development. Moreover, multiple LecRKs appear to be induced upon treatment with elicitors and pathogen infection. Variation in gene expression was also analysed in seedlings of diverse Arabidopsis accessions. Taken together, this study provides a genome-wide overview of the LecRK gene family and an up-to-date classification using a novel and systematic gene nomenclature.
Gordon D. Brown - One of the best experts on this subject based on the ideXlab platform.
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c type Lectin Receptors orchestrate antifungal immunity
Nature Immunology, 2012Co-Authors: Sarah E Hardison, Gordon D. BrownAbstract:Immunity to pathogens critically requires pattern-recognition Receptors (PRRs) to trigger intracellular signaling cascades that initiate and direct innate and adaptive immune responses. For fungal infections, these responses are primarily mediated by members of the C-type Lectin Receptor family. In this Review, we highlight recent advances in the understanding of the roles and mechanisms of these multifunctional Receptors, explore how these PRRs orchestrate antifungal immunity and briefly discuss progress in the use of these Receptors as targets for antifungal and other vaccines.
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the c type Lectin Receptor clec9a mediates antigen uptake and cross presentation by human blood bdca3 myeloid dendritic cells
Blood, 2012Co-Authors: Gerty Schreibelt, Gordon D. Brown, Lieke J J Klinkenberg, Luis J Cruz, Paul J Tacken, Jurjen Tel, Martin Kreutz, Gosse J Adema, Carl G Figdor, Jolanda I M De VriesAbstract:CLEC9A is a recently discovered C-type Lectin Receptor involved in sensing necrotic cells. In humans, this Receptor is selectively expressed by BDCA3(+) myeloid dendritic cells (mDCs), which have been proposed to be the main human cross-presenting mDCs and may represent the human homologue of murine CD8(+) DCs. In mice, it was demonstrated that antigens delivered with antibodies to CLEC9A are presented by CD8(+) DCs to both CD4(+) and CD8(+) T cells and induce antitumor immunity in a melanoma model. Here we assessed the ability of CLEC9A to mediate antigen presentation by human BDCA3(+) mDCs, which represent < 0.05% of peripheral blood leukocytes. We demonstrate that CLEC9A is only expressed on immature BDCA3(+) mDCs and that cell surface expression is lost after TLR-mediated maturation. CLEC9A triggering via antibody binding rapidly induces Receptor internalization but does not affect TLR-induced cytokine production or expression of costimulatory molecules. More importantly, antigens delivered via CLEC9A antibodies to BDCA3(+) mDCs are presented by both MHC class I (cross-presentation) and MHC class II to antigen-specific T cells. We conclude that CLEC9A is a promising target for in vivo antigen delivery in humans to increase the efficiency of vaccines against infectious or malignant diseases.
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syk coupled c type Lectins in immunity
Trends in Immunology, 2011Co-Authors: Ann M Kerrigan, Gordon D. BrownAbstract:The Syk-coupled C-type Lectin Receptor Dectin-1 was the first non-Toll like Receptor described that could mediate its own intracellular signalling. It was initially identified as important for the innate recognition of and response to fungal pathogens but later studies revealed that it is also involved in triggering adaptive immune responses. It subsequently emerged that Dectin-1 is one of a number of spleen tyrosine kinase-coupled C-type Lectin Receptors that have been implicated not just in fungal immunity, but also in viral, mycobacterial and helminth infections. Here, we consider the ability of these Receptors to trigger different aspects of immunity and highlight their emerging roles in a number of infection scenarios.
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c type Lectin Receptors in antifungal immunity
Trends in Microbiology, 2008Co-Authors: Janet A Willment, Gordon D. BrownAbstract:Fungal infections represent a significant health burden, especially in immunocompromised individuals, yet many of the underlying immunological mechanisms involved in the recognition and control of these pathogens are unclear. The identification of the Toll-like Receptors (TLRs) has shed new insights on innate microbial recognition and the initiation of immune responses; however, recent evidence indicates that the 'non-TLR' Receptors also have a significant role in these processes, particularly in antifungal immunity. Of interest are members of the C-type Lectin-Receptor family, including the mannose Receptor, dendritic cell-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing non-integrin (DC-SIGN), Dectin-1, Dectin-2 and the colLectins. Here, we review the roles of each of these Receptors, describing how they contribute to fungal recognition, uptake and killing and also participate in the induction and/or modulation of the host immune response.
Jonas Aretz - One of the best experts on this subject based on the ideXlab platform.
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high affinity sugar ligands of c type Lectin Receptor langerin
Biochimica et Biophysica Acta, 2018Co-Authors: Tetsuya Hirayama, Masahiro Nagata, Hendra S Ismanto, Bernd Lepenies, Jonas Aretz, Yasuhiko Kizuka, Reiko Fujinawa, Yoshiki Yamaguchi, Christoph RademacherAbstract:Abstract Background Langerin, a C-type Lectin Receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti-inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application. Methods We performed binding analysis between purified long and short forms of langerin and a series of KS disaccharide components. We also chemically synthesized oligomeric derivatives of L4 to develop a new high-affinity ligand of langerin. Results We show that the binding critically requires the 6-sulfation of Gal and that the long form of langerin displays higher affinity than the short form. The synthesized trimeric (also designated as triangle or Tri) and polymeric (pendant) L4 derivatives displayed over 1000-fold higher affinity toward langerin than monomeric L4. The pendant L4, but not the L4 monomer, was found to effectively transduce langerin signaling in a model cell system. Conclusions L4 is a specific ligand for langerin. Oligomerization of L4 unit increased the affinity toward langerin. General significance These results suggest that oligomeric L4 derivatives will be useful for clarifying the langerin functions and for the development of new glycan-based anti-inflammatory drugs.
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bacterial polysaccharide specificity of the pattern recognition Receptor langerin is highly species dependent
Journal of Biological Chemistry, 2017Co-Authors: Jessica Schulze, Jonas Aretz, Jonas Hanske, Henrik Schmidt, Ryan Mcbride, Bernhard LollAbstract:Abstract The recognition of pathogen surface polysaccharides by glycan-binding proteins is a cornerstone of innate host defense. Many members of the C-type Lectin Receptor family serve as pattern recognition Receptors facilitating pathogen uptake, antigen processing, and immunomodulation. Despite the high evolutionary pressure in host-pathogen interactions, it is still widely assumed that genetic homology conveys similar specificities. Here, we investigate the ligand specificities of the human and murine forms of the myeloid C-type Lectin Receptor langerin for simple and complex ligands augmented by structural insight into murine langerin. Although the two homologs share the same three-dimensional structure and recognize simple ligands identically, a screening of more than 300 bacterial polysaccharides revealed highly diverging avidity and selectivity for larger and more complex glycans. Structural and evolutionary conservation analysis identified a highly variable surface adjacent to the canonic binding site, potentially forming a secondary site of interaction for large glycans.
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computational and experimental prediction of human c type Lectin Receptor druggability
Frontiers in Immunology, 2014Co-Authors: Jonas Aretz, Eike-christian Wamhoff, Jonas Hanske, Dario Heymann, Christoph RademacherAbstract:Mammalian C-type Lectin Receptors (CTLRS) are involved in many aspects of immune cell regulation such as pathogen recognition, clearance of apoptotic bodies, and lymphocyte homing. Despite a great interest in modulating CTLR recognition of carbohydrates, the number of specific molecular probes is limited. To this end, we predicted the druggability of a panel of 22 CTLRs using DoGSiteScorer. The computed druggability scores of most structures were low, characterizing this family as either challenging or even undruggable.To further explore these findings, we employed a fluorine-based nuclear magnetic resonance screening of fragment mixtures against DC-SIGN, a Receptor of pharmacological interest. To our surprise, we found many fragment hits associated with the carbohydrate recognition site (hit rateD 13.5%). A surface plasmon resonance-based follow-up assay confirmed 18 of these fragments (47%) and equilibrium dissociation constants were determined. Encouraged by these findings we expanded our experimental druggability prediction to Langerin and MCL and found medium to high hit rates as well, being 15.7 and 10.0%, respectively. Our results highlight limitations of current in silico approaches to druggability assessment, in particular, with regard to carbohydrate-binding proteins. In sum, our data indicate that small molecule ligands for a larger panel of CTLRs can be developed.
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computational and experimental prediction of human c type Lectin Receptor druggability
Frontiers in Immunology, 2014Co-Authors: Jonas Aretz, Eike-christian Wamhoff, Jonas Hanske, Dario Heymann, Christoph RademacherAbstract:Mammalian C-type Lectin Receptors (CTLRS) are involved in many aspects of immune cell regulation such as pathogen recognition, clearance of apoptotic bodies, and lymphocyte homing. Despite a great interest in modulating CTLR recognition of carbohydrates, the number of specific molecular probes is limited. To this end, we predicted the druggability of a panel of 22 CTLRs using DoGSiteScorer. The computed druggability scores of most structures were low, characterizing this family as either challenging or even undruggable.To further explore these findings, we employed a fluorine-based nuclear magnetic resonance screening of fragment mixtures against DC-SIGN, a Receptor of pharmacological interest. To our surprise, we found many fragment hits associated with the carbohydrate recognition site (hit rateD 13.5%). A surface plasmon resonance-based follow-up assay confirmed 18 of these fragments (47%) and equilibrium dissociation constants were determined. Encouraged by these findings we expanded our experimental druggability prediction to Langerin and MCL and found medium to high hit rates as well, being 15.7 and 10.0%, respectively. Our results highlight limitations of current in silico approaches to druggability assessment, in particular, with regard to carbohydrate-binding proteins. In sum, our data indicate that small molecule ligands for a larger panel of CTLRs can be developed.