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

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.