期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 292, 期 41, 页码 16933-16941出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M117.800847
关键词
immunology; lectin; polysaccharide; receptor; signal transduction; glucan
资金
- Advanced Research and Development Programs for Medical Innovation (AMED-CREST) [26110009, 17K15730]
- Research on Development of New Drugs Grants from Japan Agency for Medical Research and Development (AMED) [16ak0101010h0005, 17933742]
- Takeda Science Foundation
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, Glu(2) and Pro(5), 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, Lys(2) and Ser(5), 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.
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