Phylogenetic and structural insights into the origin of C-type lectin Mincle in vertebrates

• Published in: Immunogenetics (New York) Vol. 77; no. 1; p. 18
• Main Authors: Ito, Taiki, Guenther, Carla, Ishikawa, Eri, Yabuki, Takae, Nagae, Masamichi, Nakatani, Yoichiro, Yamasaki, Sho
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2025; Springer Nature B.V
• Subjects: Allergology; Amino Acid Sequence; Amphibians; Animals; Binding; Biomedical and Life Sciences; Biomedicine; Cell Biology; Crystal structure; Damage; Disaccharides; Evolution, Molecular; Fc receptors; Gene Function; Glycolipids; Homeostasis; Human Genetics; Humans; Immunity, Innate; Immunology; Lectins; Lectins, C-Type - chemistry; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Macrophages; Mammals; Metabolites; Models, Molecular; Monosaccharides; Original; Original Article; Pathogens; Phylogeny; Receptors; Reptiles; Reptiles & amphibians; Sugar; Vertebrates; Vertebrates - genetics; Vertebrates - immunology; Vertebrates; C-type lectin receptors; Ligand specificity; Molecular phylogenetics; Crystal structure; FcRγ
• ISSN: 0093-7711; 1432-1211; 1432-1211
• DOI: 10.1007/s00251-025-01375-x

Our bodies are continuously exposed to injurious insults by infection and tissue damage, which are primarily sensed by innate immune receptors to maintain homeostasis. Among such receptors is macrophage-inducible C-type lectin (Mincle, gene symbol CLEC4E ), a member of the C-type lectin receptor (CLR) family, which functions as an immune sensor for both pathogens and damaged self. To monitor these injurious stimuli, Mincle recognizes disaccharide-based pathogen-derived glycolipids and monosaccharide-based intracellular metabolites, such as β-glucosylceramide. Mincle is well-conserved among mammals; however, there are questions that remain unclear, such as from which lower vertebrate did it arise and whether the original ligand was self or non-self. Here, we found homologues of Mincle and its signaling subunit Fc receptor γ chain (FcRγ) in lower vertebrates, such as reptiles, amphibians, and fishes. The crystal structure of a Mincle homologue revealed that fish Mincle possesses a narrower sugar-binding pocket than that of mammalian Mincle, and accommodates only monosaccharide moieties. These results suggest that Mincle may have evolved from a self-recognizing receptor, and its sugar-binding pocket widened during evolution, presumably to adapt to disaccharide-based glycolipids derived from life-threatening pathogens.