title: Importance of extra- and intracellular domains of TLR1 and TLR2 in NFkappa B signaling.
abstract: Recognition of ligands by toll-like receptor (TLR) 2 requires interactions with other TLRs. TLRs form a combinatorial repertoire to discriminate between the diverse microbial ligands. Diversity results from extracellular and intracellular interactions of different TLRs. This paper demonstrates that TLR1 and TLR2 are required for ara-lipoarabinomannan- and tripalmitoyl cysteinyl lipopeptide-stimulated cytokine secretion from mononuclear cells. Confocal microscopy revealed that TLR1 and TLR2 cotranslationally form heterodimeric complexes on the cell surface and in the cytosol. Simultaneous cross-linking of both receptors resulted in ligand-independent signal transduction. Using chimeric TLRs, we found that expression of the extracellular domains along with simultaneous expression of the intracellular domains of both TLRs was necessary to achieve functional signaling. The domains from each receptor did not need to be contained within a single contiguous protein. Chimeric TLR analysis further defined the toll/IL-1R domains as the area of crucial intracellular TLR1-TLR2 interaction.
authors.affiliation: Department of Medicine, University of Massachusetts Medical Center, Worcester, MA 01605-2324, USA.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Sandor
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Fabio
authors.initials: F
authors.lastname: Re
authors.forename: Leisa
authors.initials: L
authors.lastname: Mandell
authors.forename: Galina
authors.initials: G
authors.lastname: Repik
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.forename: Robert W
authors.initials: RW
authors.lastname: Finberg
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000276:immunology; D006801:Humans; D007424:Intracellular Fluid / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015054:Zymosan / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D015054:Zymosan