ID   ECSIT_MOUSE             Reviewed;         435 AA.
AC   Q9QZH6; Q91V53;
DT   26-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT   26-JUN-2007, sequence version 2.
DT   24-JAN-2024, entry version 132.
DE   RecName: Full=Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial {ECO:0000305};
DE   AltName: Full=Protein SITPEC;
DE   Flags: Precursor;
GN   Name=Ecsit {ECO:0000312|MGI:MGI:1349469}; Synonyms=Sitpec;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH TRAF6 AND MAP3K1, FUNCTION,
RP   ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY.
RC   TISSUE=Liver;
RX   PubMed=10465784; DOI=10.1101/gad.13.16.2059;
RA   Kopp E., Medzhitov R., Carothers J., Xiao C., Douglas I., Janeway C.A.,
RA   Ghosh S.;
RT   "ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal
RT   transduction pathway.";
RL   Genes Dev. 13:2059-2071(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Czech II, and FVB/N; TISSUE=Mammary tumor;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH SMAD1 AND SMAD4,
RP   ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY.
RX   PubMed=14633973; DOI=10.1101/gad.1145603;
RA   Xiao C., Shim J.-H., Klueppel M., Zhang S.S.-M., Dong C., Flavell R.A.,
RA   Fu X.-Y., Wrana J.L., Hogan B.L.M., Ghosh S.;
RT   "Ecsit is required for Bmp signaling and mesoderm formation during mouse
RT   embryogenesis.";
RL   Genes Dev. 17:2933-2949(2003).
RN   [4]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brown adipose tissue, Heart, Kidney, Liver, Spleen, and Testis;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
RN   [5]
RP   INTERACTION WITH TRIM59.
RX   PubMed=22588174; DOI=10.1016/j.bbrc.2012.05.028;
RA   Kondo T., Watanabe M., Hatakeyama S.;
RT   "TRIM59 interacts with ECSIT and negatively regulates NF-kappaB and IRF-
RT   3/7-mediated signal pathways.";
RL   Biochem. Biophys. Res. Commun. 422:501-507(2012).
RN   [6]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=29514094; DOI=10.1016/j.celrep.2018.02.051;
RA   Carneiro F.R.G., Lepelley A., Seeley J.J., Hayden M.S., Ghosh S.;
RT   "An Essential Role for ECSIT in Mitochondrial Complex I Assembly and
RT   Mitophagy in Macrophages.";
RL   Cell Rep. 22:2654-2666(2018).
CC   -!- FUNCTION: Adapter protein that plays a role in different signaling
CC       pathways including TLRs and IL-1 pathways or innate antiviral induction
CC       signaling (PubMed:10465784). Plays a role in the activation of NF-
CC       kappa-B by forming a signal complex with TRAF6 and TAK1/MAP3K7 to
CC       activate TAK1/MAP3K7 leading to activation of IKKs. Once ubiquitinated,
CC       interacts with the dissociated RELA and NFKB1 proteins and translocates
CC       to the nucleus where it induces NF-kappa-B-dependent gene expression.
CC       Plays a role in innate antiviral immune response by bridging the
CC       pattern recognition receptors RIGI and MDA5/IFIT1 to the MAVS complex
CC       at the mitochondrion (By similarity). Promotes proteolytic activation
CC       of MAP3K1. Involved in the BMP signaling pathway (PubMed:14633973).
CC       Required for normal embryonic development (By similarity).
CC       {ECO:0000250|UniProtKB:Q9BQ95, ECO:0000269|PubMed:10465784,
CC       ECO:0000269|PubMed:14633973}.
CC   -!- FUNCTION: As part of the MCIA complex, involved in the assembly of the
CC       mitochondrial complex I. {ECO:0000269|PubMed:29514094}.
CC   -!- SUBUNIT: Interacts with MAP3K1, SMAD4 and TRAF6. Interacts with SMAD1
CC       only after BMP4-treatment (PubMed:14633973, PubMed:10465784). Part of
CC       the mitochondrial complex I assembly/MCIA complex that comprises at
CC       least the core subunits TMEM126B, NDUFAF1, ECSIT and ACAD9 and
CC       complement subunits such as COA1 and TMEM186. Interacts with NDUFAF1.
CC       Interacts with ACAD9. Interacts with TRIM59 (PubMed:22588174).
CC       Interacts with TMEM70 and TMEM242 (By similarity). Interacts (when
CC       ubiquitinated) with NF-kappa-B subunits RELA and NFKB1 (By similarity).
CC       Interacts with RIGI, IFIT1 and MAVS; these interactions promote RLR-
CC       mediated type I IFN induction (By similarity). Interacts with SQSTM1;
CC       this interaction inhibits TLR4 signaling via functional regulation of
CC       the TRAF6-ECSIT complex (By similarity). Interacts with cereblon/CRBN;
CC       this interaction inhibits the ubiquitination of ECSIT (By similarity).
CC       {ECO:0000250|UniProtKB:Q9BQ95, ECO:0000269|PubMed:10465784,
CC       ECO:0000269|PubMed:14633973, ECO:0000269|PubMed:22588174}.
CC   -!- INTERACTION:
CC       Q9QZH6; P70196: Traf6; NbExp=5; IntAct=EBI-527020, EBI-448028;
CC       Q9QZH6; P62991: Ubc; NbExp=2; IntAct=EBI-527020, EBI-413074;
CC       Q9QZH6; Q9Y4K3: TRAF6; Xeno; NbExp=2; IntAct=EBI-527020, EBI-359276;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9BQ95}. Nucleus
CC       {ECO:0000250|UniProtKB:Q9BQ95}. Mitochondrion
CC       {ECO:0000250|UniProtKB:Q9BQ95}.
CC   -!- TISSUE SPECIFICITY: Detected in heart, brain, lung, liver, skeletal
CC       muscle, kidney and testis. Detected in embryonic mesoderm and epiblast,
CC       and in extraembryonic ectoderm. {ECO:0000269|PubMed:10465784,
CC       ECO:0000269|PubMed:14633973}.
CC   -!- PTM: Ubiquitinated on Lys-372; leading to translocation in the nucleus
CC       together with RELA and NFKB1 and expression of NF-kappa-B-dependent
CC       genes. {ECO:0000250|UniProtKB:Q9BQ95}.
CC   -!- DISRUPTION PHENOTYPE: Macrophages lacking ECSIT exhibit profound
CC       disruption of mitochondrial complex I/CI. Deletion lead to increased
CC       dependence on glycolysis and mitochondrial respiratory chain
CC       dysfunction. {ECO:0000269|PubMed:29514094}.
CC   -!- SIMILARITY: Belongs to the ECSIT family. {ECO:0000305}.
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DR   EMBL; AF182510; AAF01219.1; -; mRNA.
DR   EMBL; BC004583; AAH04583.1; -; mRNA.
DR   EMBL; BC016424; AAH16424.1; -; mRNA.
DR   CCDS; CCDS22920.1; -.
DR   RefSeq; NP_001240826.1; NM_001253897.1.
DR   RefSeq; NP_001240827.1; NM_001253898.1.
DR   RefSeq; NP_036159.1; NM_012029.2.
DR   RefSeq; XP_006510433.1; XM_006510370.3.
DR   RefSeq; XP_011240840.1; XM_011242538.2.
DR   AlphaFoldDB; Q9QZH6; -.
DR   BioGRID; 205076; 6.
DR   CORUM; Q9QZH6; -.
DR   DIP; DIP-33901N; -.
DR   IntAct; Q9QZH6; 16.
DR   STRING; 10090.ENSMUSP00000136247; -.
DR   iPTMnet; Q9QZH6; -.
DR   PhosphoSitePlus; Q9QZH6; -.
DR   EPD; Q9QZH6; -.
DR   jPOST; Q9QZH6; -.
DR   MaxQB; Q9QZH6; -.
DR   PaxDb; 10090-ENSMUSP00000137424; -.
DR   PeptideAtlas; Q9QZH6; -.
DR   ProteomicsDB; 277544; -.
DR   Pumba; Q9QZH6; -.
DR   DNASU; 26940; -.
DR   GeneID; 26940; -.
DR   KEGG; mmu:26940; -.
DR   UCSC; uc009ons.2; mouse.
DR   AGR; MGI:1349469; -.
DR   CTD; 51295; -.
DR   MGI; MGI:1349469; Ecsit.
DR   eggNOG; KOG3941; Eukaryota.
DR   InParanoid; Q9QZH6; -.
DR   OrthoDB; 4098911at2759; -.
DR   PhylomeDB; Q9QZH6; -.
DR   TreeFam; TF314943; -.
DR   Reactome; R-MMU-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR   Reactome; R-MMU-6799198; Complex I biogenesis.
DR   Reactome; R-MMU-975138; TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
DR   Reactome; R-MMU-975871; MyD88 cascade initiated on plasma membrane.
DR   BioGRID-ORCS; 26940; 17 hits in 78 CRISPR screens.
DR   ChiTaRS; Ecsit; mouse.
DR   PRO; PR:Q9QZH6; -.
DR   Proteomes; UP000000589; Unplaced.
DR   RNAct; Q9QZH6; Protein.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; ISO:MGI.
DR   GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR   GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0005667; C:transcription regulator complex; IDA:MGI.
DR   GO; GO:0003682; F:chromatin binding; IDA:MGI.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR   GO; GO:0060090; F:molecular adaptor activity; ISO:MGI.
DR   GO; GO:0030509; P:BMP signaling pathway; IDA:MGI.
DR   GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR   GO; GO:0001707; P:mesoderm formation; IMP:MGI.
DR   GO; GO:0051341; P:regulation of oxidoreductase activity; ISS:UniProtKB.
DR   GO; GO:0061635; P:regulation of protein complex stability; ISS:UniProtKB.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:MGI.
DR   GO; GO:0034142; P:toll-like receptor 4 signaling pathway; ISO:MGI.
DR   GO; GO:0007178; P:transmembrane receptor protein serine/threonine kinase signaling pathway; IDA:MGI.
DR   InterPro; IPR029342; ECIST_C.
DR   InterPro; IPR010418; ECSIT.
DR   InterPro; IPR046448; ECSIT_N.
DR   PANTHER; PTHR13113; ECSIT EVOLUTIONARILY CONSERVED SIGNALING INTERMEDIATE IN TOLL PATHWAYS; 1.
DR   PANTHER; PTHR13113:SF1; EVOLUTIONARILY CONSERVED SIGNALING INTERMEDIATE IN TOLL PATHWAY, MITOCHONDRIAL; 1.
DR   Pfam; PF14784; ECSIT_C; 1.
DR   Pfam; PF06239; ECSIT_N; 1.
DR   SMART; SM01284; ECSIT_Cterm; 1.
PE   1: Evidence at protein level;
KW   Cytoplasm; Immunity; Innate immunity; Isopeptide bond; Mitochondrion;
KW   Nucleus; Reference proteome; Transit peptide; Ubl conjugation.
FT   TRANSIT         1..48
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000255"
FT   CHAIN           49..435
FT                   /note="Evolutionarily conserved signaling intermediate in
FT                   Toll pathway, mitochondrial"
FT                   /id="PRO_0000291987"
FT   REGION          401..435
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   CROSSLNK        372
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000250|UniProtKB:Q9BQ95"
FT   CONFLICT        75
FT                   /note="L -> S (in Ref. 1; AAF01219)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   435 AA;  49799 MW;  A2ABA68F1E2C6BF3 CRC64;
     MSWVQVNLLV RSLSRGWGGL CRPALSGTPF AQVSLQALRG LHCSAATHKD EPWLVPRPPE
     PQRKPIKVPA MHEDLFKPSG NRERDKASFL NAVRSFGAHN VRKRGHVDFI YLALRKMPEF
     GVERDLSVYN LLLDVFPKEV FRPRNVIQRI FVHYPRQQEC GVAVLEQMER HGVMPSAETE
     FLLIQIFGRK SYPMLKFLRM KLWFTRFKNI NPYPVPRDLP QDPLDLAKLG LRHMEPDLSA
     KVTVYQMSLP SDSTGMEDPT QPHIVGIQSP DQQAALARHN PSRPVFVEGP FPLWLRNKCV
     YYHILRADLP PPEEEKVEEI PEEWELYYPQ KLDLEYSRSG WDDYEFDVDE VTEGPVFAMC
     MAGAHDQATL IKWIQGLQET NPTLAQIPVV FRLARSTGEL LTTSRLEGQS PPHSPPKGPE
     EDDETIQAEQ QQGQS
//