Chaperones and transport proteins regulate TLR4 trafficking and activation.
TLR4/MD-2 plays an important role in the inflammatory responses against lipopolysaccharide (LPS), a principal membrane component in Gram-negative bacteria. LPS recognition by TLR4/MD-2 is followed by the homotypic interaction of TLR4 (TLR4 dimerization) on the cell surface, leading to the activation of the downstream signaling pathways. The activated TLR4 is transported from plasma membrane to lysosomes, where TLR4 is degraded as a mechanism terminating LPS responses. TLR4 endocytosis is dependent on clathrin-coated vesicles. On the other hand, chaperones play an important role in TLR4 trafficking from endoplasmic reticulum (ER) to cell surface, where TLR4 recognizes LPS and activates. Chaperone gp96 and newly identified chaperone PRAT4A differentially regulate TLR4 translocation to the cell surface. In this review, we discuss TLR4 localization from endoplasmic reticulum to the cell surface and from the cell surface to endosome/lysosome that regulate TLR4 activation.
Saitoh
Shin-Ichiroh
S
Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108-8639, Japan. shinss@ims.u-tokyo.ac.jp
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism*; D011992:Endosomes / Q000276:immunology*; D016905:Gram-Negative Bacterial Infections / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D051197:Toll-Like Receptor 4; C053387:endoplasmin