Structural Analysis of Lipopolysaccharide-receptor on hemocytes of horseshoe crab

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The innate immune system is a sensitive non-self-recognizing cascade triggered by microbial cell wall constituents called pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharides (LPS) of Gram-negative bacteria, β-1,3-glucans of fungi, and peptidoglycans of Gram-positive bacteria. These PAMPs are recognized via a set of germ line-encoded receptros of innate immune system called pattern recognition receptors. Recent studies have revealed that insects and mannals conserve a signaling pathway of the innate immune system through cell-surface receptors, Toll and Toll-like receptors (TLRs). In mammals, TLRs on specialized antigen-presenting cells function as signal transducers by way of NF-kB, leading to the production of pro-inflammatory cytokines and the expression of constimulatory molecules on the cell surface, which are necessary to activate naive T cells; TLRs are possibly assembled at the cell membrane as signaling receptor complexes. In the horseshoe crab innate immunity, LPS-induced exocytosis of granular hemocytes is a key phenomenon to fight infectious microorganisms: the stimulation by LPS induces the secretion of various defense molecules stored in granules of hemocytes. Here we show that a granular component factor C, an LPS-recognizing serine protease zymogen initiating the hemolymph coagulation cascade, also exists on the surface of hemocytes. Our data demonstrate that the complex of the activated factor C with LPS is not required but the proteolytic activity is required and sufficient to trigger the exocytosis through a heterotrimeric GTP-binding protein-mediating signaling pathway. We conclude that the serine protease zymogen on hemocytes functions as a pattern recognition receptor for LPS.