TRAF6_PIG
ID TRAF6_PIG Reviewed; 541 AA.
AC A7XUJ6;
DT 09-FEB-2010, integrated into UniProtKB/Swiss-Prot.
DT 23-OCT-2007, sequence version 1.
DT 03-AUG-2022, entry version 122.
DE RecName: Full=TNF receptor-associated factor 6;
DE EC=2.3.2.27;
DE AltName: Full=E3 ubiquitin-protein ligase TRAF6;
DE AltName: Full=RING-type E3 ubiquitin transferase TRAF6 {ECO:0000305};
GN Name=TRAF6;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Wang D., Xiao S., Fang L.;
RL Submitted (AUG-2007) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: E3 ubiquitin ligase that, together with UBE2N and UBE2V1,
CC mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains
CC conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2. Also
CC mediates ubiquitination of free/unanchored polyubiquitin chain that
CC leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and
CC JUN (By similarity). Seems to also play a role in dendritic cells (DCs)
CC maturation and/or activation (By similarity). Represses c-Myb-mediated
CC transactivation, in B-lymphocytes. Adapter protein that seems to play a
CC role in signal transduction initiated via TNF receptor, IL-1 receptor
CC and IL-17 receptor (By similarity). Regulates osteoclast
CC differentiation by mediating the activation of adapter protein complex
CC 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together
CC with MAP3K8, mediates CD40 signals that activate ERK in B-cells and
CC macrophages, and thus may play a role in the regulation of
CC immunoglobulin production (By similarity).
CC {ECO:0000250|UniProtKB:P70196, ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27;
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Homotrimer. Homooligomer. N-terminal region is dimeric while
CC C-terminal region is trimeric; maybe providing a mode of
CC oligomerization. Upon IL1B treatment, forms a complex with PELI1,
CC IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and
CC TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1
CC prevents the complex formation and hence negatively regulates IL1R-TLR
CC signaling and eventually NF-kappa-B-mediated gene expression. Binds to
CC TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2,
CC IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting
CC protein TRIP and TNF receptor associated protein TDP2. Interacts with
CC IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary
CC complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and
CC PELI3. Binds UBE2V1. Interacts with TAX1BP1. Interacts with ZNF675.
CC Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and
CC TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts
CC with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3.
CC Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts
CC with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity).
CC Interacts with RSAD2/viperin (By similarity). Interacts (via C-
CC terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By
CC similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts
CC with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts
CC (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3
CC (via N-terminus). Interacts with TICAM2. Interacts with CARD14.
CC Interacts with CD40 and MAP3K8; the interaction is required for ERK
CC activation (By similarity). Interacts with TICAM1 and this interaction
CC is enhanced in the presence of WDFY1. Interacts with TANK; this
CC interaction increases in response to DNA damage. Interacts with USP10;
CC this interaction increases in response to DNA damage. Interacts with
CC ZC3H12A; this interaction increases in response to DNA damage and is
CC stimulated by TANK (By similarity). Interacts with WDFY3 (By
CC similarity). Interacts with TRIM13 (By similarity). Interacts with GPS2
CC (By similarity). Interacts (via C-terminus) with SASH1. Interacts with
CC LRRC19. Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70.
CC Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-
CC linked ubiquitination of ULK1 (By similarity).
CC {ECO:0000250|UniProtKB:P70196, ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Y4K3}.
CC Cytoplasm, cell cortex {ECO:0000250|UniProtKB:Q9Y4K3}. Nucleus
CC {ECO:0000250|UniProtKB:Q9Y4K3}. Lipid droplet
CC {ECO:0000250|UniProtKB:P70196}. Note=RSAD2/viperin recruits it to the
CC lipid droplet. {ECO:0000250|UniProtKB:P70196}.
CC -!- DOMAIN: The coiled coil domain mediates homo- and hetero-
CC oligomerization. {ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- DOMAIN: The MATH/TRAF domain binds to receptor cytoplasmic domains.
CC {ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- PTM: Sumoylated on Lys-125, Lys-143 and Lys-472 with SUMO1.
CC {ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- PTM: Polyubiquitinated on Lys-125 by TRAF3IP2; after cell stimulation
CC with IL17A (By similarity). Polyubiquitinated; after cell stimulation
CC with IL1B or TGFB. This ligand-induced cell stimulation leads to
CC dimerization/oligomerization of TRAF6 molecules, followed by auto-
CC ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6
CC activation. This 'Lys-63' site-specific poly-ubiquitination appears to
CC be associated with the activation of signaling molecules. Endogenous
CC autoubiquitination occurs only for the cytoplasmic form.
CC Deubiquitinated by USP10 in a TANK-dependent manner, leading to the
CC negative regulation of NF-kappa-B signaling upon DNA damage. LRRC19
CC induces 'Lys-63' ubiquitination (By similarity).
CC {ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- SIMILARITY: Belongs to the TNF receptor-associated factor family. A
CC subfamily. {ECO:0000305}.
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DR EMBL; EU095967; ABU75303.1; -; mRNA.
DR RefSeq; NP_001098756.1; NM_001105286.1.
DR RefSeq; XP_005652858.1; XM_005652801.1.
DR RefSeq; XP_013845523.1; XM_013990069.1.
DR AlphaFoldDB; A7XUJ6; -.
DR BMRB; A7XUJ6; -.
DR SMR; A7XUJ6; -.
DR BioGRID; 1148792; 1.
DR STRING; 9823.ENSSSCP00000029003; -.
DR PaxDb; A7XUJ6; -.
DR Ensembl; ENSSSCT00000038108; ENSSSCP00000034114; ENSSSCG00000038082.
DR Ensembl; ENSSSCT00025072870; ENSSSCP00025031583; ENSSSCG00025053171.
DR Ensembl; ENSSSCT00040020989; ENSSSCP00040008813; ENSSSCG00040015563.
DR Ensembl; ENSSSCT00045010582; ENSSSCP00045007210; ENSSSCG00045006364.
DR Ensembl; ENSSSCT00050070036; ENSSSCP00050030107; ENSSSCG00050051437.
DR Ensembl; ENSSSCT00055029378; ENSSSCP00055023384; ENSSSCG00055014879.
DR Ensembl; ENSSSCT00060033021; ENSSSCP00060014161; ENSSSCG00060024340.
DR Ensembl; ENSSSCT00070002699; ENSSSCP00070002244; ENSSSCG00070001436.
DR Ensembl; ENSSSCT00070002709; ENSSSCP00070002254; ENSSSCG00070001436.
DR GeneID; 396629; -.
DR KEGG; ssc:396629; -.
DR CTD; 7189; -.
DR VGNC; VGNC:94365; TRAF6.
DR eggNOG; KOG0297; Eukaryota.
DR GeneTree; ENSGT00940000155426; -.
DR HOGENOM; CLU_021061_5_0_1; -.
DR InParanoid; A7XUJ6; -.
DR OMA; WMQKNNQ; -.
DR OrthoDB; 918518at2759; -.
DR TreeFam; TF321154; -.
DR Reactome; R-SSC-1257604; PIP3 activates AKT signaling.
DR Reactome; R-SSC-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR Reactome; R-SSC-193692; Regulated proteolysis of p75NTR.
DR Reactome; R-SSC-202424; Downstream TCR signaling.
DR Reactome; R-SSC-209543; p75NTR recruits signalling complexes.
DR Reactome; R-SSC-209560; NF-kB is activated and signals survival.
DR Reactome; R-SSC-2871837; FCERI mediated NF-kB activation.
DR Reactome; R-SSC-450302; activated TAK1 mediates p38 MAPK activation.
DR Reactome; R-SSC-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
DR Reactome; R-SSC-5607764; CLEC7A (Dectin-1) signaling.
DR Reactome; R-SSC-5689880; Ub-specific processing proteases.
DR Reactome; R-SSC-5689896; Ovarian tumor domain proteases.
DR Reactome; R-SSC-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-SSC-9020702; Interleukin-1 signaling.
DR Reactome; R-SSC-937039; IRAK1 recruits IKK complex.
DR Reactome; R-SSC-937041; IKK complex recruitment mediated by RIP1.
DR Reactome; R-SSC-937042; IRAK2 mediated activation of TAK1 complex.
DR Reactome; R-SSC-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex.
DR Reactome; R-SSC-9645460; Alpha-protein kinase 1 signaling pathway.
DR Reactome; R-SSC-975138; TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
DR Reactome; R-SSC-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
DR Reactome; R-SSC-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation.
DR Reactome; R-SSC-975871; MyD88 cascade initiated on plasma membrane.
DR UniPathway; UPA00143; -.
DR Proteomes; UP000008227; Chromosome 2.
DR Proteomes; UP000314985; Chromosome 2.
DR Bgee; ENSSSCG00000038082; Expressed in heart left ventricle and 43 other tissues.
DR ExpressionAtlas; A7XUJ6; baseline and differential.
DR GO; GO:0035631; C:CD40 receptor complex; IEA:Ensembl.
DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005811; C:lipid droplet; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0042826; F:histone deacetylase binding; IEA:Ensembl.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; IEA:Ensembl.
DR GO; GO:0043422; F:protein kinase B binding; IEA:Ensembl.
DR GO; GO:0047485; F:protein N-terminus binding; IEA:Ensembl.
DR GO; GO:0031996; F:thioesterase binding; IEA:Ensembl.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:Ensembl.
DR GO; GO:0032813; F:tumor necrosis factor receptor superfamily binding; IBA:GO_Central.
DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IEA:Ensembl.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IEA:Ensembl.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IEA:Ensembl.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; IEA:Ensembl.
DR GO; GO:0045453; P:bone resorption; IEA:Ensembl.
DR GO; GO:0048468; P:cell development; IEA:Ensembl.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0097400; P:interleukin-17-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
DR GO; GO:0001503; P:ossification; IEA:Ensembl.
DR GO; GO:0030316; P:osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IEA:Ensembl.
DR GO; GO:0032743; P:positive regulation of interleukin-2 production; IEA:Ensembl.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IBA:GO_Central.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IEA:Ensembl.
DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IEA:Ensembl.
DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0002726; P:positive regulation of T cell cytokine production; IEA:Ensembl.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:2000679; P:positive regulation of transcription regulatory region DNA binding; IEA:Ensembl.
DR GO; GO:0051865; P:protein autoubiquitination; IEA:Ensembl.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:0002637; P:regulation of immunoglobulin production; IEA:Ensembl.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0042088; P:T-helper 1 type immune response; IEA:Ensembl.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IBA:GO_Central.
DR CDD; cd03776; MATH_TRAF6; 1.
DR Gene3D; 2.60.210.10; -; 1.
DR Gene3D; 3.30.40.10; -; 3.
DR InterPro; IPR002083; MATH/TRAF_dom.
DR InterPro; IPR043211; TNF_rcpt-assoc_TRAF.
DR InterPro; IPR012227; TNF_rcpt-assoc_TRAF_met.
DR InterPro; IPR008974; TRAF-like.
DR InterPro; IPR027139; TRAF6.
DR InterPro; IPR037309; TRAF6_MATH.
DR InterPro; IPR041310; TRAF6_Z2.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR InterPro; IPR001293; Znf_TRAF.
DR PANTHER; PTHR10131; PTHR10131; 1.
DR PANTHER; PTHR10131:SF131; PTHR10131:SF131; 1.
DR Pfam; PF18048; TRAF6_Z2; 1.
DR Pfam; PF02176; zf-TRAF; 1.
DR PIRSF; PIRSF015614; TRAF; 1.
DR SMART; SM00061; MATH; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS50144; MATH; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
DR PROSITE; PS50145; ZF_TRAF; 2.
PE 2: Evidence at transcript level;
KW Coiled coil; Cytoplasm; DNA damage; Immunity; Isopeptide bond;
KW Lipid droplet; Metal-binding; Nucleus; Osteopetrosis; Reference proteome;
KW Repeat; Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc;
KW Zinc-finger.
FT CHAIN 1..541
FT /note="TNF receptor-associated factor 6"
FT /id="PRO_0000391610"
FT DOMAIN 369..518
FT /note="MATH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00129"
FT ZN_FING 71..110
FT /note="RING-type; degenerate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 151..203
FT /note="TRAF-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT ZN_FING 204..260
FT /note="TRAF-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT REGION 1..373
FT /note="Interaction with TAX1BP1"
FT /evidence="ECO:0000250"
FT REGION 374..541
FT /note="Interaction with TANK"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3"
FT COILED 312..367
FT /evidence="ECO:0000255"
FT CROSSLNK 125
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250"
FT CROSSLNK 125
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3"
FT CROSSLNK 143
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT CROSSLNK 472
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
SQ SEQUENCE 541 AA; 61266 MW; CCA939106D3476BE CRC64;
MSLLHCENSC GSSQSESDCC AAMAASSCGA AAKDDGVSGT ASTGNLSSSF MEEIQGYDVE
FDPPLESKYE CPICLMALRE AVQTPCGHRF CKACIIKSIR DAGHKCPVDN EILLENQLFP
DNFAKREILS LTVKCPNVGC LHKMELRHLE DHQAHCEFAL MNCPQCQRPF QKCQLNIHIL
KECPRRQVSC VNCAVSMAFE DKEIHDQNCP LANVICEYCN TVLIREQMPN HYDLDCPTAP
VPCTFSTFGC HEKMQRNHLA RHLQENTQSH MRMMAQALQG LSLAVAPVPQ RDMLPYDSSP
LSRISSGCCS DQNFQETIQQ LEGRLVRQDH QIRELTAKME TQSMYVSELK RTIRSLEDKV
AEIEAQQCNG IYIWKIGNFG MHLKSQEEEK PVVIHSPGFY TGKPGYKLCM RLHLQLPTAQ
RCANYISLFV HTMQGEYDSH LPWPFQGTIR LTILDQSEAP IRQNHEEIMD AKPELLAFQR
PTIPRNPKGF GYVTFMHLDA LRQRTFIKDD TLLVRCEVST RFDMGSLRRE GFQPRSTDSG
T
