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J Biol Chem. 2014 Dec 19;289(51):35205-14. doi: 10.1074/jbc.M114.597187. Epub 2014 Nov 4.

TAK1-ECSIT-TRAF6 complex plays a key role in the TLR4 signal to activate NF-κB.

Author information

1
From the Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
2
the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065.
3
the Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 echun@hsph.harvard.edu.
4
From the Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea, thylee@skku.edu.

Abstract

ECSIT (evolutionarily conserved signaling intermediate in Toll pathways) is known as a multifunctional regulator in different signals, including Toll-like receptors (TLRs), TGF-β, and BMP. Here, we report a new regulatory role of ECSIT in TLR4-mediated signal. By LPS stimulation, ECSIT formed a high molecular endogenous complex including TAK1 and TRAF6, in which ECSIT interacted with each protein and regulated TAK1 activity, leading to the activation of NF-κB. ECSIT-knockdown THP-1 (ECSIT(KD) THP-1) cells exhibited severe impairments in NF-κB activity, cytokine production, and NF-κB-dependent gene expression, whereas those were dramatically restored by reintroduction of wild type (WT) ECSIT gene. Interestingly, ECSIT mutants, which lack a specific interacting domain for either TAK1 or TRAF6, could not restore these activities. Moreover, no significant changes in both NF-κB activity and cytokine production induced by TLR4 could be seen in TAK1(KD) or TRAF6(KD) THP-1 cells transduced by WT ECSIT, strongly suggesting the essential requirement of TAK1-ECSIT-TRAF6 complex in TLR4 signaling. Taken together, our data demonstrate that the ECSIT complex, including TAK1 and TRAF6, plays a pivotal role in TLR4-mediated signals to activate NF-κB.

KEYWORDS:

Cytokine; ECSIT; Inflammation; Innate Immunity; NF-kappaB; Signal Transduction; TNF Receptor-associated Factor 6; Toll-like Receptors; Transforming Growth Factor-β-activated Kinase 1

PMID:
25371197
PMCID:
PMC4271209
DOI:
10.1074/jbc.M114.597187
[Indexed for MEDLINE]
Free PMC Article

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