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Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity.

The EMBO journal | Feb 22, 2006

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.

Pubmed ID: 16467847 RIS Download

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