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Published on: July 26, 2017
Chaperones and transport proteins regulate TLR4 trafficking and activation
1Division 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
Immunobiology
|March 3, 2009
Summary
Toll-like receptor 4 (TLR4) and MD-2 mediate inflammatory responses to lipopolysaccharide (LPS). Chaperones like gp96 and PRAT4A regulate TLR4 trafficking, influencing its cell surface activation and lysosomal degradation.
Area of Science:
- Immunology
- Cell Biology
Background:
- Toll-like receptor 4 (TLR4) complexed with MD-2 is crucial for sensing lipopolysaccharide (LPS), a key component of Gram-negative bacteria.
- LPS recognition triggers TLR4 dimerization on the cell surface, initiating downstream inflammatory signaling cascades.
Purpose of the Study:
- To review the dynamic localization of TLR4 from the endoplasmic reticulum to the cell surface and its subsequent trafficking to endosomes/lysosomes.
- To elucidate the role of chaperones in regulating TLR4 translocation and activation.
Main Methods:
- Discussion of TLR4 trafficking pathways, including endocytosis via clathrin-coated vesicles.
- Analysis of the differential roles of chaperones gp96 and PRAT4A in TLR4 cell surface presentation.
Main Results:
- TLR4 undergoes regulated transport from the plasma membrane to lysosomes for degradation, a process essential for terminating inflammatory responses.
- Chaperones gp96 and PRAT4A exhibit distinct functions in controlling TLR4 movement from the endoplasmic reticulum to the cell surface.
Conclusions:
- TLR4 localization dynamics, encompassing ER-to-cell surface transport and cell surface-to-lysosome trafficking, are critical regulators of LPS-induced inflammatory activation.
- Understanding these trafficking mechanisms provides insights into controlling innate immune responses mediated by TLR4.
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