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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.

Pubmed ID: 16467847


  • Husebye H
  • Halaas Ø
  • Stenmark H
  • Tunheim G
  • Sandanger Ø
  • Bogen B
  • Brech A
  • Latz E
  • Espevik T


The EMBO journal

Publication Data

February 22, 2006

Associated Grants


Mesh Terms

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