ECSIT

{{Short description|Protein-coding gene in the species Homo sapiens}}

Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial (ECSIT), also known as SITPEC, is a protein that in humans is encoded by the ECSIT gene.{{Cite web|url=https://www.uniprot.org/uniprot/Q9BQ95|title=ECSIT - Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial precursor - Homo sapiens (Human) - ECSIT gene & protein|website=uniprot.org|language=en|access-date=2018-07-27}} ECSIT is a cytosolic adaptor protein involved in inflammatory responses, embryonic development, and the assembly and stabilization of mitochondrial NADH:ubiquinone oxidoreductase (complex I).{{cite journal | vauthors = Vogel RO, Janssen RJ, van den Brand MA, Dieteren CE, Verkaart S, Koopman WJ, Willems PH, Pluk W, van den Heuvel LP, Smeitink JA, Nijtmans LG | title = Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly | journal = Genes & Development | volume = 21 | issue = 5 | pages = 615–24 | date = March 2007 | pmid = 17344420 | pmc = 1820902 | doi = 10.1101/gad.408407 }}

Structure

ECSIT is located on the p arm of chromosome 19 in position 13.2 and has 9 exons.{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/51295|title=ECSIT ECSIT signalling integrator [Homo sapiens (human)] - Gene - NCBI|website=ncbi.nlm.nih.gov|access-date=2018-07-30}} The ECSIT gene produces a 49 kDa protein composed of 431 amino acids.{{Cite web|url=https://amino.heartproteome.org/web/protein/Q9BQ95|title=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information|last=Yao|first=Daniel|website=amino.heartproteome.org|access-date=2018-07-27|archive-date=2018-07-30|archive-url=https://web.archive.org/web/20180730234910/https://amino.heartproteome.org/web/protein/Q9BQ95|url-status=dead}} ECSIT's interactions with p65/p50 NF-κB proteins is dependent on lysine 372 ubiquitination.{{cite journal | vauthors = Mi Wi S, Park J, Shim JH, Chun E, Lee KY | title = Ubiquitination of ECSIT is crucial for the activation of p65/p50 NF-κBs in Toll-like receptor 4 signaling | journal = Molecular Biology of the Cell | volume = 26 | issue = 1 | pages = 151–60 | date = January 2015 | pmid = 25355951 | pmc = 4279226 | doi = 10.1091/mbc.E14-08-1277 }} ECSIT also contains an N-terminal targeting signal that causes it to localize to mitochondria where only the 45 kDa mitochondrial ECSIT is found to interact.

Function

ECSIT has been found to play multiple roles in cell-signaling, including those that utilize Toll-like receptors (TLRs), TGF-β, and BMP. ECSIT plays a regulatory role as part of the TAK1-ECSIT-TRAF6 complex that is involved in the activation of NF-κB by the TLR4 signal and through its interactions with TRIM59 to negatively regulate NF-κB, IRF-3, and IRF-7-mediated signal pathways.{{cite journal | vauthors = Kondo T, Watanabe M, Hatakeyama S | title = TRIM59 interacts with ECSIT and negatively regulates NF-κB and IRF-3/7-mediated signal pathways | journal = Biochemical and Biophysical Research Communications | volume = 422 | issue = 3 | pages = 501–7 | date = June 2012 | pmid = 22588174 | doi = 10.1016/j.bbrc.2012.05.028 | hdl = 2115/49795 | s2cid = 16613194 | hdl-access = free }}{{cite journal | vauthors = Wi SM, Moon G, Kim J, Kim ST, Shim JH, Chun E, Lee KY | title = TAK1-ECSIT-TRAF6 complex plays a key role in the TLR4 signal to activate NF-κB | journal = The Journal of Biological Chemistry | volume = 289 | issue = 51 | pages = 35205–14 | date = December 2014 | pmid = 25371197 | pmc = 4271209 | doi = 10.1074/jbc.M114.597187 | doi-access = free }} Additionally, ECSIT appears to contribute to bactericidal activity in TLR signaling through its interaction with tumor necrosis factor receptor-associated factor 6 (TRAF6). Importantly, ubiquitination of ECSIT has shown itself to be necessary for the activation of p65/p50 NF-κBs in TLR4 signaling. Functioning as a scaffold protein, ECSIT is also essential for the association of RIG-I-like receptors (RIG-I or MDA5) to VISA. The bridging of these receptors to VISA is an important signaling event used in innate antiviral responses.{{cite journal | vauthors = Lei CQ, Zhang Y, Li M, Jiang LQ, Zhong B, Kim YH, Shu HB | title = ECSIT bridges RIG-I-like receptors to VISA in signaling events of innate antiviral responses | journal = Journal of Innate Immunity | volume = 7 | issue = 2 | pages = 153–64 | date = 2015 | pmid = 25228397 | doi = 10.1159/000365971 | pmc = 6738808 }} Apart from inflammatory and immune responses, ECSIT, in its 45 kDa, mitochondrial form helps maintain assembly chaperone NDUFAF1's stable presence in the mitochondrion. Through this interaction, ECSIT is demonstrated to play an important role in NADH:ubiquinone oxidoreductase (complex I) assembly and stabilization. Finally, it is important to note that ECSIT is required for normal embryonic development.

Interactions

ECSIT has 136 protein-protein interactions, with 53 of them being co-complex interactions.{{citation needed|date=August 2018}}{{cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=ECSIT | title = 136 binary interactions found for search term ECSIT | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-25 }}

In addition to TAK1, TRAF6, TRIM59, RIG-I-like receptors, VISA, and NDUFAF1 interactions, ECSIT can interact with MAP3K1 and SMAD4, and is a part of the mitochondrial complex I assembly (MCIA) complex.

ECSIT

Structure

Function

Interactions

References

Further reading