Molecular mechanism for innate recognition of microbial products by toll-like receptors

The Toll family of receptors (Toll-like receptor, TLR) plays an essential role in innate recognition of microbial products. TLR is a type I transmembrane protein that contains a large, leucine-rich repeats in the extracellular region and a Toll/IL-1 receptor homology (TIR) domain in the cytoplasmic region. Microbial membranes are recognized by TLR4, TLR2, TLR1, and TLR6, whereas DNA or RNA derived from pathogens are sensed by TLR3, TLR7, TLR8 and TLR9. Despite identification of microbial ligands for TLRs, molecular mechanisms underlying microbial recognition by Toll-like receptors remain enigmatic. Lipopolysaccharide (LPS) is one of the most immunostimulatory glycolipids constituting the outer membrane of the Gram-negative bacteria. LPS in the membrane is transferred to CD14 by LPS-binding protein (LBP). CD14 then transfers LPS to the receptor complex consisting of TLR4 and MD-2. MD-2 is an extracellular molecule that is associated with the extracellular domain of TLR4 and essential for LPS responses, since mice lacking MD-2 are hyporesponsive to LPS. LPS directly interacts with cell surface TLR4/MD-2, which leads to ligand-dependent oligomerization of TLR4 and subsequent signaling. Soluble MD-2 as well as TLR4/MD-2 was reported to bind to LPS, and subsequent ligand-induced oligomerization of TLR4 was regulated by MD-2. These results demonstrate roles for MD-2 as a coreceptor in microbial recognition of LPS. TLR4, therefore, requires additional molecules such as MD-2, CD14, and LBP for processing and recognizing LPS. It is well possible for other TLRs to require similar molecules in microbial recognition.