Mechanism regulating cell surface expression and activation of Toll-like receptor 4.
The Toll family of receptors senses microbial invasion and activates defense responses. Toll-like receptor 4 (TLR4) is a member of the Toll family that senses lipopolysaccharide (LPS), a principal membrane component from Gram-negative bacteria. LPS is known as an endotoxin that strongly activates immune cells such as macrophages and dendritic cells. LPS recognition by TLR4 requires an additional accessory molecule, MD-2. MD-2 is associated with the extracellular portion of TLR4, directly binds to LPS, and regulates subsequent LPS-induced TLR4 clustering. LPS recognition occurs on the cell surface. The subcellular distribution of TLR was shown to influence TLR responses. An endoplasmic reticulum (ER) chaperone, glycoprotein 96, is required for the stability of TLR4 and the formation of a TLR4/MD-2 complex in ER. MD-2 facilitates TLR4 glycosylation and its trafficking to the cell surface. Recently, another molecule, a protein associated with Toll-like receptor 4 (PRAT4A), was shown to play a critical role in cell surface expression of TLR4. These molecules control LPS responsiveness by regulating the subcellular distribution of TLR4.
Saitoh
Shin-Ichiroh
S
Division of Infectious Genetics, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. shinss@ims.u-tokyo.ac.jp
Miyake
Kensuke
K
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism*; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D051218:Lymphocyte Antigen 96 / Q000096:biosynthesis / Q000276:immunology; D021381:Protein Transport; D015398:Signal Transduction / Q000276:immunology; D013347:Subcellular Fractions / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000276:immunology
D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4