Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity
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ABSTRACT:
PROVIDER: PRJNA386319 | ENA |
REPOSITORIES: ENA
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Project description:C-type lectin receptors (CLRs) are a large family of immunoreceptors that recognizes polysaccharides exposed on pathogens and triggers innate immune responses. However, the ligand spectrums of the whole members have not been fully understood. In this study, we found that seaweed-derived fucan activates cells expressing human Dectin-1 but not mouse Dectin-1. In fucan, low-valency β-glucan appeared to represent this activity, as the ligand activity was eliminated by the treatment of westase, a β-glucanase. Another low-valency β-glucan, laminarin, also acts as an agonist on human Dectin-1 but not for mouse Dectin-1, whereas high-valency β-glucan curdlan activated both human and mouse Dectin-1. Reciprocal mutagenesis analysis revealed that the ligand-binding domain of human Dectin-1 did not determine its unique sensitivity to low-valency β-glucan. Rather, its intracellular domain contributes to render human Dectin-1 reactive to low-valency β-glucan. Within the hDectin-1 intracellular domain, only two amino acids, Glu2 and Pro5, were sufficient to confer sensitivity on mouse Dectin-1. Conversely, the introduction of mouse-type amino acids, Lys2 and Ser5, to human Dectin-1 reduced the reactivity. These results suggest that the intracellular domain, but not the ligand binding domain, of Dectin-1 modulate their functions which determine the ligand spectrum.
2017-08-25 | GSE98825 | GEO
Project description:C-type lectin receptors (CLRs) are a large family of immunoreceptors that recognizes polysaccharides exposed on pathogens and triggers innate immune responses. However, the ligand spectrums of the whole members have not been fully understood. In this study, we found that seaweed-derived fucan activates cells expressing human Dectin-1 but not mouse Dectin-1. In fucan, low-valency β-glucan appeared to represent this activity, as the ligand activity was eliminated by the treatment of westase, a β-glucanase. Another low-valency β-glucan, laminarin, also acts as an agonist on human Dectin-1 but not for mouse Dectin-1, whereas high-valency β-glucan curdlan activated both human and mouse Dectin-1. Reciprocal mutagenesis analysis revealed that the ligand-binding domain of human Dectin-1 did not determine its unique sensitivity to low-valency β-glucan. Rather, its intracellular domain contributes to render human Dectin-1 reactive to low-valency β-glucan. Within the hDectin-1 intracellular domain, only two amino acids, Glu2 and Pro5, were sufficient to confer sensitivity on mouse Dectin-1. Conversely, the introduction of mouse-type amino acids, Lys2 and Ser5, to human Dectin-1 reduced the reactivity. These results suggest that the intracellular domain, but not the ligand binding domain, of Dectin-1 modulate their functions which determine the ligand spectrum.
2017-08-25 | GSE98814 | GEO
Project description:C-type lectin receptors (CLRs) comprise a large family of immunoreceptors that recognize polysaccharide ligands exposed on pathogen surfaces and are conserved among mammals. However, interspecies differences in their ligand spectrums are not fully understood. Dectin-1 is a well-characterized CLR that recognizes ?-glucan. We report here that seaweed-derived fucan activates cells expressing human Dectin-1 but not mouse Dectin-1. Low-valency ?-glucan components within fucan appeared to be responsible for this activation, as the ligand activity was eliminated by ?-glucanase treatment. The low-valency ?-glucan laminarin also acted as an agonist for human Dectin-1 but not for mouse Dectin-1, whereas the high-valency ?-glucan curdlan activated both human and mouse Dectin-1. Reciprocal mutagenesis analysis revealed that the ligand-binding domain of human Dectin-1 does not determine its unique sensitivity to low-valency ?-glucan. Rather, we found that its intracellular domain renders human Dectin-1 reactive to low-valency ?-glucan ligand. Substitution with two amino acids, Glu2 and Pro5, located in the human Dectin-1 intracellular domain was sufficient to confer sensitivity to low-valency ?-glucan in mouse Dectin-1. Conversely, the introduction of mouse-specific amino acids, Lys2 and Ser5, to human Dectin-1 reduced the reactivity to low-valency ?-glucan. Indeed, low-valency ligands induced a set of proinflammatory genes in human but not mouse dendritic cells. These results suggest that the intracellular domain, not ligand-binding domain, of Dectin-1 determines the species-specific ligand profile.
| S-EPMC5641891 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-08-25 | GSE98826 | GEO
Project description:Cells of the innate immune system retain memory of prior exposures through a process known as innate immune training. b-glucan, a Dectin-1 ligand purified from the Candida albicans cell wall, has been one of the most widely utilized and well-characterized ligands for inducing innate immune memory. However, many Dectin-1 agonists exist, and it is not known whether all Dectin-1 ligands produce the same phenotype. Using a well-established in vitro model of trained immunity, we compared two commercially available Dectin-1 agonists with the gold standard b-glucan represented in the literature. We found that depleted zymosan, a b-glucan purified from the Saccharomyces cerevisiae cell wall through alkali treatment, produced near identical training effects as C. albicans b-glucan. However, untreated zymosan produced a distinct training effect from b-glucans at both the transcript and cytokine level. Training with zymosan diminished, rather than potentiated, induction of key cytokines such as TNF, IL-12, and IL-6. Zymosan activated NFkB and AP-1 transcription factors more strongly than b-glucans. The addition of the toll-like receptor (TLR) ligand Pam3CSK4 was sufficient to convert the training effect of b-glucans to a phenotype resembling training with zymosan. We conclude that differential activation of TLR signaling pathways determines the phenotype of innate immune training induced by Dectin-1. These findings bring clarity to the specific question of which Dectin-1 agonists produce prototypical training effects and provides broader insight into how signaling networks regulate innate immune training at large.
2024-01-29 | GSE242947 | GEO
Project description:Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity [human]
| PRJNA386315 | ENA
Project description:Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity [mouse]
| PRJNA386316 | ENA
Project description:Rat mast cell line RBL-2H3 was analyzed to investigate the molecular mechanism of Dectin-1-mediated activation and responses of mast cells. Dectin-1-mediated signaling stimulated characteristic gene expression, such as MCP-1, IL-4, IL-13, TNF-αand Nfkbiz. RBL-2H3 cell line stably expressing Dectin-1 was established. Non-stimulated cells (control) compared to Dectin-1-stimulated (Curdlan) cells in order to comfirm Dectin-1-mediated signaling-inducible genes. Dectin-1-stimulated cells compared to Syk inhibitor R406-pretreated cells in order to examine the importance of Syk for Dectin-1-mediated gene up-regulations.
2014-03-27 | E-GEOD-56246 | biostudies-arrayexpress
Project description:Purpose: To characterize Card9-dependent and Card9-independent Dectin-1 mediated gene expression changes in neutrophils and to compare response to Dectin-1 stimulation in neutrophils and macrophages. Method: BM neutrophils from WT and Card9-/- mice were isolated by MACS column purification and treated with or without the Dectin-1 agonist, curdlan for 3 hrs. WT BM-derived macrophages were also treated with or without curdlan for 3hrs before sample collection. Results: We identified both Card9-dependent and Card9-independent gene expression changes with Dectin-1 stimulation in neutrophils. We also identified cell-type specific differences in the response to Dectin-1 stimulation in neutrophils and macrophages. Conclusions: Dectin-1 stimulation induces significant gene expression changes regulated by either canonical Card9-dependent or non-canonical Card9-independent mechanisms.
2021-02-26 | GSE148850 | GEO
Project description:Rat mast cell line RBL-2H3 was analyzed to investigate the molecular mechanism of Dectin-1-mediated activation and responses of mast cells. Dectin-1-mediated signaling stimulated characteristic gene expression, such as MCP-1, IL-4, IL-13, TNF-αand Nfkbiz.
2014-03-27 | GSE56246 | GEO