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J Biol Chem. 2015 Feb 6;290(6):3209-22. doi: 10.1074/jbc.M114.593426. Epub 2014 Dec 11.

A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling.

Author information

1
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.
2
the Department of Medicine, Division of Infectious Diseases and Immunology, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and.
3
From the Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, and.
4
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.
5
the Center for Global Health and Diseases and Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106.
6
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.
7
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.

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.

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

PMID:
25505250
PMCID:
PMC4318996
DOI:
10.1074/jbc.M114.593426
[Indexed for MEDLINE]
Free PMC Article

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