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.