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

• DOI: 10.1038/sj.emboj.7600991
• Publication Date: 2006-02-09T05:15:26Z
• Authors: Harald Husebye; Øyvind Halaas; Harald Stenmark; Gro Tunheim; Øystein Sandanger; Bjarne Bogen; Andreas Brech; Eicke Latz; Terje Espevik
• Keywords: CD4-Positive T-Lymphocytes; Dynamins; Lipopolysaccharides; 0301 basic medicine; Antigen Presentation; Endosomal Sorting Complexes Required for Transport; Histocompatibility Antigens Class II; Biological Transport, Active; Phosphoproteins; Clathrin; Endocytosis; Immunity, Innate; Cell Line; Toll-Like Receptor 4; 03 medical and health sciences; HLA Antigens; Humans; Signal Transduction

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.