title: Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells.
abstract: Intracellular Toll-like receptor 3 (TLR3), TLR7, and TLR9 localize in endosomes and recognize single-stranded RNA and nucleotides from viruses and bacteria. This interaction induces their conformational changes resulting in the production of proinflammatory cytokines and upregulation of cell surface molecules. TLR9 requires a proteolytic cleavage for its signaling. Here, we report that myeloid and plasmacytoid dendritic cells (DCs) deficient for the asparagine endopeptidase (AEP), a cysteine lysosomal protease, showed a decrease in the secretion of proinflammatory cytokines in response to TLR9 stimulation in vitro and in vivo. Upon stimulation, full-length TLR9 was cleaved into a 72 kDa fragment and this processing was strongly reduced in DCs lacking AEP. Processed TLR9 coeluted with the adaptor molecule MyD88 and AEP after size exclusion chromatography. When expressed in AEP-deficient DCs, the 72 kDa proteolytic fragment restored TLR9 signaling. Thus, our results identify an endocytic protease playing a critical role in TLR processing and signaling in DCs.
authors.affiliation: Institut Curie, U932, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Fernando E
authors.initials: FE
authors.lastname: Sepulveda
authors.forename: Sophia
authors.initials: S
authors.lastname: Maschalidi
authors.forename: Renaud
authors.initials: R
authors.lastname: Colisson
authors.forename: Lea
authors.initials: L
authors.lastname: Heslop
authors.forename: Cristina
authors.initials: C
authors.lastname: Ghirelli
authors.forename: Emna
authors.initials: E
authors.lastname: Sakka
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Lennon-Duménil
authors.forename: Sebastian
authors.initials: S
authors.lastname: Amigorena
authors.forename: Lucien
authors.initials: L
authors.lastname: Cabanie
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Manoury
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D000099240:Asparaginyl Endopeptidase
chemical_list: D002403:Cathepsins; D003546:Cysteine Endopeptidases; D051217:Toll-Like Receptor 9; D000099240:Asparaginyl Endopeptidase