Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity.
Immune responses are initiated when molecules of microbial origin are sensed by the Toll-like receptors (TLRs). We now report the identification of essential molecular components for the trafficking of the lipopolysaccharide (LPS) receptor complex. LPS was endocytosed by a receptor-mediated mechanism dependent on dynamin and clathrin and colocalized with TLR4 ... on early/sorting endosomes. TLR4 was ubiquitinated and associated with the ubiquitin-binding endosomal sorting protein hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs. Inhibition of endocytosis and endosomal sorting increased LPS signaling. Finally, the LPS receptor complex was sorted to late endosomes/lysosomes for degradation and loading of associated antigens onto HLA class II molecules for presentation to CD4+ T cells. Our results show that endosomal trafficking of the LPS receptor complex is essential for signal termination and LPS-associated antigen presentation, thus controlling both innate and adaptive immunity through TLR4.
Mesh Terms:
Antigen Presentation, Biological Transport, Active, CD4-Positive T-Lymphocytes, Cell Line, Clathrin, Dynamins, Endocytosis, Endosomal Sorting Complexes Required for Transport, HLA Antigens, Histocompatibility Antigens Class II, Humans, Immunity, Innate, Lipopolysaccharides, Phosphoproteins, Signal Transduction, Toll-Like Receptor 4
Antigen Presentation, Biological Transport, Active, CD4-Positive T-Lymphocytes, Cell Line, Clathrin, Dynamins, Endocytosis, Endosomal Sorting Complexes Required for Transport, HLA Antigens, Histocompatibility Antigens Class II, Humans, Immunity, Innate, Lipopolysaccharides, Phosphoproteins, Signal Transduction, Toll-Like Receptor 4
EMBO J.
Date: Feb. 22, 2006
PubMed ID: 16467847
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