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| Subject Categories: Membranes & Transport | Immunology |
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| The EMBO Journal
(2006) 25, 683–692, doi:10.1038/sj.emboj.7600991 Published online 9 February 2006 |
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| Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity |
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| Harald Husebye1, 5, Øyvind Halaas1, 5, Harald Stenmark1, 3, Gro Tunheim2, Øystein Sandanger1, Bjarne Bogen2, Andreas Brech3, Eicke Latz4 and Terje Espevik1 |
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1 Institute of Cancer Research and Molecular Medicine, The Norwegian University of Science and Technology, Trondheim, Norway 2 Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway 3 Department of Biochemistry, The Norwegian Radiumhospital, Oslo, Norway 4 Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA To whom correspondence should be addressed Terje Espevik, Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7489 Trondheim, Norway. Tel.: +47 7359 8668; Fax: +47 7359 8801; E-mail: terje.espevik@ntnu.no 5 These authors contributed equally to this work Received 26 August 2005; Accepted 13 January 2006; Published online 9 February 2006. |
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| Abstract |
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| 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. |
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| Keywords: antigen presentation, endocytosis, sorting, Toll-like receptor (TLR) |
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