title: A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling.
abstract: Toll-like receptors (TLRs) are involved in sensing invading microbes by host innate immunity. TLR2 recognizes bacterial lipoproteins/lipopeptides, and lipopolysaccharide activates TLR4. TLR2 and TLR4 signal via the Toll/interleukin-1 receptor adaptors MyD88 and MAL, leading to NF-κB activation. TLR4 also utilizes the adaptors TRAM and TRIF, resulting in activation of interferon regulatory factor (IRF) 3. Here, we report a new role for TRAM and TRIF in TLR2 regulation and signaling. Interestingly, we observed that TLR2-mediated induction of the chemokine Ccl5 was impaired in TRAM or TRIF deficient macrophages. Inhibition of endocytosis reduced Ccl5 release, and the data also suggested that TRAM and TLR2 co-localize in early endosomes, supporting the hypothesis that signaling may occur from an intracellular compartment. Ccl5 release following lipoprotein challenge additionally involved the kinase Tbk-1 and Irf3, as well as MyD88 and Irf1. Induction of Interferon-β and Ccl4 by lipoproteins was also partially impaired in cells lacking TRIF cells. Our results show a novel function of TRAM and TRIF in TLR2-mediated signal transduction, and the findings broaden our understanding of how Toll/interleukin-1 receptor adaptor proteins may participate in signaling downstream from TLR2.
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and the KG Jebsen Center for Myeloma Research, Norwegian University of Science and Technology, N-7489 Trondheim, Norway, nadra.nilsen@ntnu.no.
authors.forename: Nadra J
authors.initials: NJ
authors.lastname: Nilsen
authors.affiliation: the Department of Medicine, Division of Infectious Diseases and Immunology, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Vladimer
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Stenvik
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and the Department of Medicine, Division of Infectious Diseases and Immunology, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and.
authors.forename: M Pontus A
authors.initials: MP
authors.lastname: Orning
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Zeid-Kilani
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and.
authors.forename: Marit
authors.initials: M
authors.lastname: Bugge
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and.
authors.forename: Bjarte
authors.initials: B
authors.lastname: Bergstroem
authors.affiliation: the Department of Medicine, Division of Infectious Diseases and Immunology, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Conlon
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and.
authors.forename: Harald
authors.initials: H
authors.lastname: Husebye
authors.affiliation: the Center for Global Health and Diseases and Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Amy G
authors.initials: AG
authors.lastname: Hise
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and the Department of Medicine, Division of Infectious Diseases and Immunology, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and the KG Jebsen Center for Myeloma Research, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.affiliation: From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and the Department of Medicine, Division of Infectious Diseases and Immunology, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and Egil.Lien@umassmed.edu.
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D050856:Interferon Regulatory Factor-1; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D017346:Protein Serine-Threonine Kinases; D018123:Receptors, Interleukin; D051195:Toll-Like Receptor 2; C494258:Irf1 protein, mouse; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C476416:Ticam2 protein, mouse; C493486:Tlr2 protein, mouse; C498588:Tbk1 protein, mouse
keywords: Innate Immunity; Interferon; Interferon Regulatory Factor (IRF); Macrophage; TIR Domain-containing Adaptor-inducing Interferon-B (TRIF); Toll-like Receptor (TLR); Toll-like Receptor 2 (TLR2); Toll-like Receptor Adaptor Molecule 2