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- Title
Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity.
- Authors
Husebye, Harald; Halaas, Øyvind; Stenmark, Harald; Tunheim, Gro; Sandanger, Øystein; Bogen, Bjarne; Brech, Andreas; Latz, Eicke; Espevik, Terje
- 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.
- Subjects
IMMUNE response; MOLECULES; ENDOTOXINS; RECEPTOR-ligand complexes; UBIQUITIN; LYSOSOMES
- Publication
EMBO Journal, 2006, Vol 25, Issue 4, p683
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/sj.emboj.7600991