title: Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting.
abstract: Toll-like receptors (TLRs) are receptors of the innate immune system responsible for recognizing pathogen-associated molecular patterns. TLR2 seems to be the most promiscuous TLR receptor able to recognize the most diverse set of pathogen-associated patterns. Its promiscuity has been attributed to its unique ability to heterodimerize with TLRs 1 and 6 and, most recently, to its association with CD36 in response to diacylated lipoproteins. Thus, it seems that TLR2 forms receptor clusters in response to different microbial ligands. In this study we investigated TLR2 cell surface heterotypic interactions in response to different ligands as well as internalization and intracellular trafficking. Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. Upon stimulation by the specific ligand, these heterodimers are recruited within lipid rafts. In contrast, heterotypic associations of TLR2/6 with CD36 are not preformed and are ligand-induced. All TLR2 receptor clusters accumulate in lipid rafts and are targeted to the Golgi apparatus. This localization and targeting is ligand-specific. Activation occurs at the cell surface, and the observed trafficking is independent of signaling.
authors.affiliation: Infection and Immunity Group, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, United Kingdom.
authors.forename: Martha
authors.initials: M
authors.lastname: Triantafilou
authors.forename: Frederick G J
authors.initials: FG
authors.lastname: Gamper
authors.forename: Rowenna M
authors.initials: RM
authors.lastname: Haston
authors.forename: Marios Angelos
authors.initials: MA
authors.lastname: Mouratis
authors.forename: Siegfried
authors.initials: S
authors.lastname: Morath
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.forename: Kathy
authors.initials: K
authors.lastname: Triantafilou
mesh_terms: D018955:CD36 Antigens / Q000096:biosynthesis*; D002462:Cell Membrane / Q000378:metabolism* / Q000382:microbiology; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008024:Ligands; D021962:Membrane Microdomains / Q000737:chemistry; D009174:Mycoplasma / Q000378:metabolism; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000378:metabolism; D051194:Toll-Like Receptor 1 / Q000737:chemistry / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000737:chemistry / Q000502:physiology*; D051216:Toll-Like Receptor 6 / Q000737:chemistry / Q000502:physiology*
chemical_list: D018955:CD36 Antigens; D008024:Ligands; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6