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

Harald Husebye; Øyvind Halaas; Harald Stenmark; Gro Tunheim; Øystein Sandanger; Bjarne Bogen; Andreas Brech; Eicke Latz; Terje Espevik

doi:10.1038/sj.emboj.7600991

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

EMBO J. 2006 Feb 22;25(4):683-92. doi: 10.1038/sj.emboj.7600991. Epub 2006 Feb 9.

Authors

Harald Husebye¹, Øyvind Halaas, Harald Stenmark, Gro Tunheim, Øystein Sandanger, Bjarne Bogen, Andreas Brech, Eicke Latz, Terje Espevik

Affiliation

¹ Institute of Cancer Research and Molecular Medicine, The Norwegian University of Science and Technology, Trondheim, Norway.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigen Presentation / drug effects
Antigen Presentation / immunology*
Biological Transport, Active / immunology
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / immunology
Cell Line
Clathrin / immunology
Dynamins / immunology
Endocytosis / drug effects
Endocytosis / immunology*
Endosomal Sorting Complexes Required for Transport
HLA Antigens / immunology
Histocompatibility Antigens Class II / immunology
Humans
Immunity, Innate / drug effects
Immunity, Innate / immunology*
Lipopolysaccharides / immunology*
Lipopolysaccharides / pharmacology
Phosphoproteins / immunology
Signal Transduction / drug effects
Signal Transduction / immunology*
Toll-Like Receptor 4 / immunology*

Substances

Clathrin
Endosomal Sorting Complexes Required for Transport
HLA Antigens
Histocompatibility Antigens Class II
Lipopolysaccharides
Phosphoproteins
TLR4 protein, human
Toll-Like Receptor 4
hepatocyte growth factor-regulated tyrosine kinase substrate
lipopolysaccharide, Escherichia coli O111 B4
Dynamins