title: CD14 controls the LPS-induced endocytosis of Toll-like receptor 4.
abstract: The transport of Toll-like Receptors (TLRs) to various organelles has emerged as an essential means by which innate immunity is regulated. While most of our knowledge is restricted to regulators that promote the transport of newly synthesized receptors, the regulators that control TLR transport after microbial detection remain unknown. Here, we report that the plasma membrane localized Pattern Recognition Receptor (PRR) CD14 is required for the microbe-induced endocytosis of TLR4. In dendritic cells, this CD14-dependent endocytosis pathway is upregulated upon exposure to inflammatory mediators. We identify the tyrosine kinase Syk and its downstream effector PLCγ2 as important regulators of TLR4 endocytosis and signaling. These data establish that upon microbial detection, an upstream PRR (CD14) controls the trafficking and signaling functions of a downstream PRR (TLR4). This innate immune trafficking cascade illustrates how pathogen detection systems operate to induce both membrane transport and signal transduction.
authors.affiliation: Harvard Medical School and Division of Gastroenterology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Zanoni
authors.forename: Renato
authors.initials: R
authors.lastname: Ostuni
authors.forename: Lorri R
authors.initials: LR
authors.lastname: Marek
authors.forename: Simona
authors.initials: S
authors.lastname: Barresi
authors.forename: Roman
authors.initials: R
authors.lastname: Barbalat
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Barton
authors.forename: Francesca
authors.initials: F
authors.lastname: Granucci
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Kagan
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D051966:Phospholipase C gamma / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D047908:Intracellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051966:Phospholipase C gamma; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C000606897:Syk protein, mouse
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