title: Intracellular Toll-like receptor recruitment and cleavage in endosomal/lysosomal organelles.
abstract: Microbial pathogens are recognized through multiple, distinct receptors such as intracellular Toll-like receptors (TLRs 3, 7, 8, 9, and 13) which reside in the endosomes and lysosomes. TLRs are sensitive to chloroquine, a lysomotropic agent that neutralizes acidic compartments indicating a role for endo/lysosomal proteases for their signaling. Indeed, upon stimulation, full-length TLR7 and 9 are cleaved into a C-terminal fragment and this processing is highly dependent on a cysteine protease named asparagine endopeptidase (AEP) in dendritic cells. A recruitment and a boost in AEP activity, which was induced shortly after TLR7 and 9 stimulation, are shown to promote TLR7 and 9 cleavage and correlate with an increased acidification in endosomes and lysosomes. Moreover, mutating a putative AEP cleavage site in TLR7 or 9 strongly decreases their signaling in DCs, suggesting perhaps a direct cleavage of TLR7 and 9 by AEP. These results demonstrate that TLR7 and 9 require a proteolytic cleavage for their signaling and identified a key endocytic protease playing a critical role in this process.
authors.affiliation: INSERM, Unité 1013, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, Paris, France; INSERM, Unité 932, Institut Curie, Paris, France.
authors.forename: Mira
authors.initials: M
authors.lastname: Tohmé
authors.affiliation: INSERM, Unité 1013, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, Paris, France. Electronic address: benedicte.manoury@inserm.fr.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Manoury
mesh_terms: D000818:Animals; D002458:Cell Fractionation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D011992:Endosomes / Q000201:enzymology* / Q000378:metabolism; D057075:Enzyme Assays; D008247:Lysosomes / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D010447:Peptide Hydrolases / Q000302:isolation & purification / Q000378:metabolism; D061251:Primary Cell Culture; D021381:Protein Transport; D059748:Proteolysis; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D051193:Toll-Like Receptors; D010447:Peptide Hydrolases
keywords: Dendritic cells; Intracellular TLRs; MHCII; MyD88; Processing; Proteases