A Role for the Adaptor Proteins TRAM and TRIF in Toll-like Receptor 2 Signaling

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2014 Dec 16

PMID 25505250

Citations 54

Authors

Nadra J Nilsen

Gregory I Vladimer

Jorgen Stenvik

M Pontus A Orning

Maria V Zeid-Kilani

Marit Bugge

Bjarte Bergstroem

Joseph Conlon

Harald Husebye

Amy G Hise

Katherine A Fitzgerald

Terje Espevik

Egil Lien

Affiliations

Soon will be listed here.

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.

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