title: TAK1-ECSIT-TRAF6 complex plays a key role in the TLR4 signal to activate NF-κB.
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.
authors.affiliation: From the Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
authors.forename: Sae Mi
authors.initials: SM
authors.lastname: Wi
authors.affiliation: From the Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
authors.forename: Gyuyoung
authors.initials: G
authors.lastname: Moon
authors.affiliation: From the Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
authors.forename: Juhong
authors.initials: J
authors.lastname: Kim
authors.affiliation: From the Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Shim
authors.affiliation: 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.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Chun
authors.affiliation: From the Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea, thylee@skku.edu.
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D046912:Multiprotein Complexes; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D000099151:MAP Kinase Kinase Kinase 7; C518657:Ecsit protein, human; C495345:TLR4 protein, human
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