Alternative titles; symbols
HGNC Approved Gene Symbol: ECSIT
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:11,505,929-11,529,134 (from NCBI)
The ECSIT protein interacts with the TLR signaling adaptor TRAF6 (602355), localizes to mitochondria, and has a role in oxidative phosphorylation complex I assembly (summary by West et al., 2011).
Using mouse Traf6 as bait in a yeast 2-hybrid screen, Kopp et al. (1999) cloned 3 splice variants of mouse Ecsit from liver and pre-B-cell cDNA libraries. The longest deduced protein contains 435 amino acids, and the variants differ in their C termini. Northern blot analysis detected a transcript of about 1.6 kb in all mouse tissues examined.
Vogel et al. (2007) stated that 10 ECSIT splice variants are predicted, but only the 2 longest have been identified in experimental studies. The longest, called variant 1, utilizes all 8 exons and encodes a deduced 431-amino acid protein with a calculated molecular mass of 50 kD. Variant 2 lacks exon 6 and encodes a deduced 382-amino acid protein with a calculated molecular mass of 33 kD. Western blot analysis of fractionated human embryonic kidney cells detected a protein of about 50 kD in the cytoplasm/nuclear fraction and a protein of about 45 kD in the mitochondrial fraction. The first 48 amino acids of ECSIT constitute a mitochondrial targeting signal.
Kopp et al. (1999) determined that mouse Ecsit is an intermediate in the activation of the Toll (see 603030)/Il1 (see 147760) pathway and regulates Mekk1 (600982) processing for activation of Nfkb (see 164011). Expression of wildtype Ecsit accelerated the processing of Mekk1, and a dominant-negative fragment of Ecsit blocked Mekk1 processing and activation of Nfkb.
Using 2-dimensional native PAGE analysis of mitochondria enriched from HEK293 and HeLa cells, Vogel et al. (2007) found that the 45-kD mitochondrial ECSIT protein, but not the 50-kD cytosolic protein, was a component of higher molecular mass complexes of about 500, 600, and 850 kD. ECSIT copurified with the mitochondrial complex I assembly chaperone NDUFAF1 (606934), and knockdown of ECSIT resulted in impaired complex I assembly and disturbed mitochondrial function.
West et al. (2011) demonstrated that engagement of a subset of Toll-like receptors (TLR1, 601194; TLR2, 603028; and TLR4, 603030) results in the recruitment of mitochondria to macrophage phagosomes and augments mitochondrial reactive oxygen species (mROS) production. This response involves translocation of a TLR signaling adaptor, TRAF6, to mitochondria, where it engages the protein ECSIT, which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase (115500) in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. West et al. (2011) concluded that their results revealed a novel pathway linking innate immune signaling to mitochondria, implicated mROS as an important component of antibacterial responses, and further established mitochondria as hubs for innate immune signaling.
Vogel et al. (2007) stated that the ECSIT gene contains 8 exons.
The International Radiation Hybrid Mapping Consortium mapped the ECSIT gene to chromosome 19 (RH98319).
Xiao et al. (2003) found that targeted disruption of Ecsit in mice led to reduced cell proliferation, altered epiblast patterning, impaired mesoderm formation, and lethality at embryonic day 7.5. The phenotype mimicked that of Bmpr1a (601299) null mice. Biochemical analysis demonstrated that Ecsit associated constitutively with Smad4 (600993) and Smad1 (601595) in a Bmp-inducible manner. Together with Smad1 and Smad4, Ecsit bound to the promoter of specific Bmp target genes. Knockdown of Ecsit expression with short hairpin RNA inhibited both Bmp and Toll signaling.
Kopp, E., Medzhitov, R., Carothers, J., Xiao, C., Douglas, I., Janeway, C. A., Ghosh, S. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev. 13: 2059-2071, 1999. [PubMed: 10465784] [Full Text: https://doi.org/10.1101/gad.13.16.2059]
Vogel, R. O., Janssen, R. J. R. J., van den Brand, M. A. M., Dieteren, C. E. J., Verkaart, S., Koopman, W. J. H., Willems, P. H. G. M., Pluk, W., van den Heuvel, L. P. W. J., Smeitink, J. A. M., Nijtmans, L. G. J. Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly. Genes Dev. 21: 615-624, 2007. [PubMed: 17344420] [Full Text: https://doi.org/10.1101/gad.408407]
West, A. P., Brodsky, I. E., Rahner, C., Woo, D. K., Erdjument-Bromage, H., Tempst, P., Walsh, M. C., Choi, Y., Shadel, G. S., Ghosh, S. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472: 476-480, 2011. [PubMed: 21525932] [Full Text: https://doi.org/10.1038/nature09973]
Xiao, C., Shim, J., Kluppel, M., Zhang, S. S.-M., Dong, C., Flavell, R. A., Fu, X.-Y., Wrana, J. L., Hogan, B. L. M., Ghosh, S. Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis. Genes Dev. 17: 2933-2949, 2003. [PubMed: 14633973] [Full Text: https://doi.org/10.1101/gad.1145603]