title: Cleaved/associated TLR3 represents the primary form of the signaling receptor.
abstract: TLR3 belongs to the family of intracellular TLRs that recognize nucleic acids. Endolysosomal localization and cleavage of intracellular TLRs play pivotal roles in signaling and represent fail-safe mechanisms to prevent self-nucleic acid recognition. Indeed, cleavage by cathepsins is required for native TLR3 to signal in response to dsRNA. Using novel Abs generated against TLR3, we show that the conserved loop exposed in LRR12 is the single cleavage site that lies between the two dsRNA binding sites required for TLR3 dimerization and signaling. Accordingly, we found that the cleavage does not dissociate the C- and N-terminal fragments, but it generates a very stable "cleaved/associated" TLR3 present in endolysosomes that recognizes dsRNA and signals. Moreover, comparison of wild-type, noncleavable, and C-terminal-only mutants of TLR3 demonstrates that efficient signaling requires cleavage of the LRR12 loop but not dissociation of the fragments. Thus, the proteolytic cleavage of TLR3 appears to fulfill function(s) other than separating the two fragments to generate a functional receptor.
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, INSERM Unité Mixte de Recherche 1052/Centre National de la Recherche Scientifique 5286, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Toscano
authors.forename: Yann
authors.initials: Y
authors.lastname: Estornes
authors.forename: François
authors.initials: F
authors.lastname: Virard
authors.forename: Alejandra
authors.initials: A
authors.lastname: Garcia-Cattaneo
authors.forename: Audrey
authors.initials: A
authors.lastname: Pierrot
authors.forename: Béatrice
authors.initials: B
authors.lastname: Vanbervliet
authors.forename: Marc
authors.initials: M
authors.lastname: Bonnin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ciancanelli
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
authors.forename: Kenji
authors.initials: K
authors.lastname: Funami
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Pin
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Toufic
authors.initials: T
authors.lastname: Renno
authors.forename: Serge
authors.initials: S
authors.lastname: Lebecque
mesh_terms: D001665:Binding Sites; D002403:Cathepsins / Q000378:metabolism; D002460:Cell Line; D020869:Gene Expression Profiling; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D059748:Proteolysis; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051196:Toll-Like Receptor 3; D002403:Cathepsins