ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway

Kopp, Elizabeth; Medzhitov, Ruslan; Carothers, James M.; Xiao, Changchun; Douglas, Iris; Janeway, Charles A.; Ghosh, Sankar

doi:10.1101/gad.13.16.2059

Cited by 309 publications

(284 citation statements)

References 52 publications

(65 reference statements)

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“…Overexpression of IPS-1 induced activation of the IFN-promoter, and coexpression of ECSIT further promoted its activation, whereas a dominant-negative form of ECSIT (ECSIT( N)) lost the transcriptional activation [15] (Fig. 2C and D).…”

Section: Ecsit Interacts With Ips-1 and Positively Regulates Rlr-medimentioning

confidence: 98%

TRIM59 interacts with ECSIT and negatively regulates NF-κB and IRF-3/7-mediated signal pathways

Kondo

Watanabe

Hatakeyama

2012

Biochemical and Biophysical Research Communications

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Innate immune responses are triggered by pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs) and then activate intracellular signaling pathways including NF-B and interferon regulatory factors. Recently, it has been reported that tripartite motif (TRIM) proteins function as crucial regulators via ubiquitin-mediated modifications for these signaling pathways. In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. Luciferase reporter assays using reporter plasmids including NF-B responsive element, interferon (IFN-) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities. Furthermore, TRIM59 inhibited phosphorylation and dimerization of IRF3 and IRF7, suggesting that TRIM59 negatively regulates upstream kinases for IRFs. These findings indicate that TRIM59 may serve as a multifunctional regulator for innate immune signaling pathways.3

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Section: Ecsit Interacts With Ips-1 and Positively Regulates Rlr-medimentioning

confidence: 98%

TRIM59 interacts with ECSIT and negatively regulates NF-κB and IRF-3/7-mediated signal pathways

Kondo

Watanabe

Hatakeyama

2012

Biochemical and Biophysical Research Communications

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“…ECSIT binds to TRAF6 and is required for TLR and interleulin-1 (IL-1) signaling, but not TNFsignaling (Kopp et al, 1999;Xiao et al, 2003). Although these studies suggested that ECSIT functions by recruiting and activating the kinase MEKK1 (mitogen activated protein kinase or ERK kinase (MEK) kinase 1) (Kopp et al, 1999;Xiao et al, 2003), the role of MEKK1 in TLR signaling remains unclear (Xia et al, 2000;Yujiri et al, 2000). MEKK3-deficient cells, however, do not transcribe IL-6 following TLR4 or IL-1R stimulation and exhibit delayed and weakened NF-kB DNA binding following lipopolysaccharide (LPS) stimulation (Huang et al, 2004).…”

Section: Toll-like Receptorsmentioning

confidence: 99%

NF-κB and the immune response

2006

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“…1 Originally identified as the predominant LPS receptor, 2,3 TLR4 has subsequently been shown to also recognize protein F from respiratory syncytial virus, 4 taxol, 5 fibronectin, 6 and endogenous HSP 60. 7 A small secreted protein, MD-2, is necessary for initiating TLR4-mediated LPS responses 8 via an intracellular pathway that involves MyD88, IL-1R-associated kinase (IRAK), Tollip, [9][10][11][12][13][14] TRAF-6, ECSIT, and TAK-1, [15][16][17] which ultimately results in activation of mitogen-activated protein (MAP) kinases and transcription factors. TLR4 also triggers the MyD88-independent pathway via recruitment of the Toll-IL-1R adapter protein (TIRAP)/MyD88-like adapter (MAL), 18,19 which mediates delayed NF-kB, MAP kinase activation, 20 and dendritic cell maturation.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of CD14, TLR4, and MD-2 in HEK 293T cells does not prevent induction of in vitro endotoxin tolerance

Medvedev

Vogel

2003

Journal of Endotoxin Research

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TLR4 and MD-2 are necessary for conferring cellular responsiveness to LPS. Prior exposure to LPS induces a transient state of cell refractoriness to subsequent LPS re-stimulation, known as `endotoxin tolerance'. While induction of LPS tolerance has been reported to correlate with down-regulation of cell surface expression of TLR4/MD-2, other mechanisms of LPS tolerance have been revealed that target intracellular intermediates downstream of the TLR4/MD-2 complex. In this study, we sought to examine whether endotoxin tolerance could be induced under conditions where expression of TLR4 and MD-2 proteins is not affected by LPS. Human HEK 293T cells are completely unresponsive to LPS, but acquire high LPS sensitivity following transient transfection with CD14, TLR4, and MD-2 (293T/CD14/TLR4/MD-2 cells), as judged by NF-κB activation, ERK 1/2 phosphorylation, and TNFα gene expression. Prior exposure of 293T/CD14/TLR4/MD-2 cells to LPS resulted in a significant decrease of LPS-mediated responses, yet failed to affect expression levels of TLR4 and MD-2. Thus, altered expression and/or function of intracellular mediators downstream of the TLR4/MD-2 complex play an important role in mediating LPS tolerance.

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ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway

Cited by 309 publications

References 52 publications

TRIM59 interacts with ECSIT and negatively regulates NF-κB and IRF-3/7-mediated signal pathways

TRIM59 interacts with ECSIT and negatively regulates NF-κB and IRF-3/7-mediated signal pathways

NF-κB and the immune response

Overexpression of CD14, TLR4, and MD-2 in HEK 293T cells does not prevent induction of in vitro endotoxin tolerance

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