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.
Husebye
Harald
H
Institute of Cancer Research and Molecular Medicine, The Norwegian University of Science and Technology, Trondheim, Norway.
Halaas
Øyvind
Ø
Stenmark
Harald
H
Tunheim
Gro
G
Sandanger
Øystein
Ø
Bogen
Bjarne
B
Brech
Andreas
A
Latz
Eicke
E
Espevik
Terje
T
D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D001693:Biological Transport, Active / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D002966:Clathrin / Q000276:immunology; D034281:Dynamins / Q000276:immunology; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology*; D056827:Endosomal Sorting Complexes Required for Transport; D006680:HLA Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D010750:Phosphoproteins / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
D002966:Clathrin; D056827:Endosomal Sorting Complexes Required for Transport; D006680:HLA Antigens; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D010750:Phosphoproteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C440499:lipopolysaccharide, Escherichia coli O111 B4; D034281:Dynamins