ID   TIFA_BOVIN              Reviewed;         185 AA.
AC   A2VDM0;
DT   26-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   20-MAR-2007, sequence version 1.
DT   03-AUG-2022, entry version 79.
DE   RecName: Full=TRAF-interacting protein with FHA domain-containing protein A {ECO:0000305};
GN   Name=TIFA {ECO:0000250|UniProtKB:Q96CG3};
OS   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1] {ECO:0000312|EMBL:AAI33303.1}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=Hereford {ECO:0000312|EMBL:AAI33303.1};
RC   TISSUE=Fetal skin {ECO:0000312|EMBL:AAI33303.1};
RG   NIH - Mammalian Gene Collection (MGC) project;
RL   Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Adapter molecule that plays a key role in the activation of
CC       pro-inflammatory NF-kappa-B signaling following detection of bacterial
CC       pathogen-associated molecular pattern metabolites (PAMPs). Promotes
CC       activation of an innate immune response by inducing the oligomerization
CC       and polyubiquitination of TRAF6, which leads to the activation of TAK1
CC       and IKK through a proteasome-independent mechanism. TIFA-dependent
CC       innate immune response is triggered by ADP-D-glycero-beta-D-manno-
CC       heptose (ADP-Heptose), a potent PAMP present in all Gram-negative and
CC       some Gram-positive bacteria: ADP-Heptose is recognized by ALPK1, which
CC       phosphorylates TIFA at Thr-9, leading to TIFA homooligomerization and
CC       subsequent activation of pro-inflammatory NF-kappa-B signaling.
CC       {ECO:0000250|UniProtKB:Q96CG3}.
CC   -!- SUBUNIT: Homooligomer; homooligomerizes following phosphorylation at
CC       Thr-9. Interacts with IRAK1, TRAF2 and TRAF6. Interacts with TIFAB;
CC       binding to TIFAB inhibits TRAF6 activation, possibly by inducing a
CC       conformational change in TIFA. Interacts with ZCCHC11; binding to
CC       ZCCHC11 suppresses the TRAF6-dependent activation of NF-kappa-B.
CC       {ECO:0000250|UniProtKB:Q96CG3}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q96CG3}.
CC       Note=Colocalizes with lysosomal marker LAMP2 following
CC       homooligomerization and subsequent activation.
CC       {ECO:0000250|UniProtKB:Q96CG3}.
CC   -!- DOMAIN: The FHA domain recognizes and binds phosphorylated Thr-9,
CC       promoting homooligomerization and subsequent activation of NF-kappa-B.
CC       {ECO:0000250|UniProtKB:Q96CG3}.
CC   -!- PTM: Phosphorylated at Thr-9 following detection of ADP-D-glycero-beta-
CC       D-manno-heptose (ADP-Heptose) by ALPK1. Phosphorylation at Thr-9 by
CC       ALPK1 leads to the formation of an intermolecular binding between the
CC       FHA domain and phosphorylated Thr-9, promoting TIFA oligomerization and
CC       TIFA-mediated NF-kappa-B activation. {ECO:0000250|UniProtKB:Q96CG3}.
CC   -!- SIMILARITY: Belongs to the TIFA family. {ECO:0000305}.
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DR   EMBL; BC133302; AAI33303.1; -; mRNA.
DR   RefSeq; NP_001075090.1; NM_001081621.1.
DR   AlphaFoldDB; A2VDM0; -.
DR   SMR; A2VDM0; -.
DR   STRING; 9913.ENSBTAP00000046244; -.
DR   PaxDb; A2VDM0; -.
DR   Ensembl; ENSBTAT00000081959; ENSBTAP00000063378; ENSBTAG00000049422.
DR   GeneID; 783855; -.
DR   KEGG; bta:783855; -.
DR   CTD; 92610; -.
DR   VEuPathDB; HostDB:ENSBTAG00000049422; -.
DR   VGNC; VGNC:35862; TIFA.
DR   eggNOG; ENOG502S0RF; Eukaryota.
DR   GeneTree; ENSGT00940000154589; -.
DR   HOGENOM; CLU_125520_0_0_1; -.
DR   InParanoid; A2VDM0; -.
DR   OMA; SIRFFNR; -.
DR   OrthoDB; 1381983at2759; -.
DR   TreeFam; TF333218; -.
DR   Proteomes; UP000009136; Chromosome 6.
DR   Bgee; ENSBTAG00000049422; Expressed in abdominal lymph node and 101 other tissues.
DR   ExpressionAtlas; A2VDM0; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0002753; P:cytoplasmic pattern recognition receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IEA:InterPro.
DR   GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR   GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR   GO; GO:0051260; P:protein homooligomerization; ISS:UniProtKB.
DR   CDD; cd00060; FHA; 1.
DR   InterPro; IPR000253; FHA_dom.
DR   InterPro; IPR008984; SMAD_FHA_dom_sf.
DR   InterPro; IPR033621; TIFA.
DR   PANTHER; PTHR31266; PTHR31266; 1.
DR   Pfam; PF00498; FHA; 1.
DR   SUPFAM; SSF49879; SSF49879; 1.
DR   PROSITE; PS50006; FHA_DOMAIN; 1.
PE   2: Evidence at transcript level;
KW   Cytoplasm; Immunity; Innate immunity; Phosphoprotein; Reference proteome.
FT   CHAIN           1..185
FT                   /note="TRAF-interacting protein with FHA domain-containing
FT                   protein A"
FT                   /id="PRO_0000320688"
FT   DOMAIN          48..104
FT                   /note="FHA"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00086"
FT   MOD_RES         9
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q96CG3"
SQ   SEQUENCE   185 AA;  21579 MW;  46A3501DD039B475 CRC64;
     MSSFEDADTE EMVTCLQMTL YHPGHQRSGI FRSIKFFNRE KLPTSEVVKF GRNSHTCNYI
     FQDKQVSRVQ FSLQVFKKFN SSVVSFEIKN MSKKTSLLVD NKELGYLNKM DLPDKCMIRF
     GDYQFLVEKE DGESLEFFEI QFSLSKKPLL QENNWLSQEP IPECGSYSSC LTQNNSPMEV
     GENEW