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TNF receptor-associated factor 6 (EC (E3 ubiquitin-protein ligase TRAF6) (RING-type E3 ubiquitin transferase TRAF6)

 TRAF6_RAT               Reviewed;         530 AA.
09-FEB-2010, integrated into UniProtKB/Swiss-Prot.
14-OCT-2008, sequence version 1.
13-NOV-2019, entry version 106.
RecName: Full=TNF receptor-associated factor 6;
AltName: Full=E3 ubiquitin-protein ligase TRAF6;
AltName: Full=RING-type E3 ubiquitin transferase TRAF6 {ECO:0000305};
Rattus norvegicus (Rat).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
Muroidea; Muridae; Murinae; Rattus.
STRAIN=Brown Norway;
Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
-!- FUNCTION: E3 ubiquitin ligase that, together with UBE2N and
UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin
chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and
AKT2. Also mediates ubiquitination of free/unanchored
polyubiquitin chain that leads to MAP3K7 activation. Mediates
activation of NF-kappa-B and JUN. May be essential for the
formation of functional osteoclasts. Seems to also play a role in
dendritic cells (DCs) maturation and/or activation. Represses c-
Myb-mediated transactivation, in B-lymphocytes. Adapter protein
that seems to play a role in signal transduction initiated via TNF
receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast
differentiation by mediating the activation of adapter protein
complex 1 (AP-1) and NF-kappa-B, in response to RANK-L
stimulation. Together with MAP3K8, mediates CD40 signals that
activate ERK in B-cells and macrophages, and thus may play a role
in the regulation of immunoglobulin production.
Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-
cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-
conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor
protein]-L-lysine.; EC=;
-!- PATHWAY: Protein modification; protein ubiquitination.
-!- SUBUNIT: Homotrimer (By similarity). Homooligomer (By similarity).
N-terminal region is dimeric while C-terminal region is trimeric;
maybe providing a mode of oligomerization. Upon IL1B treatment,
forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex
recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B
activation. Direct binding of SMAD6 to PELI1 prevents the complex
formation and hence negatively regulates IL1R-TLR signaling and
eventually NF-kappa-B-mediated gene expression. Binds to
TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17,
interacting protein TRIP and TNF receptor associated protein TDP2.
Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and
NGFR. Forms a ternary complex with SQSTM1 and PRKCZ. Interacts
with PELI2 and PELI3. Binds UBE2V1. Interacts with MAVS/IPS1.
Interacts with TAX1BP1. Interacts with IL1RL1. Interacts with
TRAFD1. Interacts with ZNF675. Interacts with AJUBA. Interacts
with TICAM2. Interacts with ZFAND5. Interacts with ARRB1 and
ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1
signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and
RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF
domains) with NUMBL (via C-terminal). Interacts (via TRAF domains)
with WDR34 (via WD domains). Interacts with RBCK1 (By similarity).
Interacts with TRAF3IP2 (By similarity). Interacts with LIMD1 (via
LIM domains) (By similarity). Interacts with RSAD2/viperin (By
similarity). Interacts with IFIT3 (via N-terminus) (By
similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the
kinase catalytic domain). Interacts with CARD14 (By similarity).
Interacts with CD40 and MAP3K8; the interaction is required for
ERK activation. Interacts with TICAM1 and this interaction is
enhanced in the presence of WDFY1 (By similarity). Interacts with
TANK; this interaction increases in response to DNA damage (By
similarity). Interacts with USP10; this interaction increases in
response to DNA damage (By similarity). Interacts with ZC3H12A;
this interaction increases in response to DNA damage and is
stimulated by TANK (By similarity). Interacts with WDFY3 (By
similarity). Interacts with TRIM13 (By similarity). Interacts with
GPS2 (By similarity). Interacts (via C-terminus) with SASH1 (By
similarity). {ECO:0000250|UniProtKB:P70196,
-!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Y4K3}.
Cytoplasm, cell cortex {ECO:0000250|UniProtKB:Q9Y4K3}. Nucleus
{ECO:0000250|UniProtKB:Q9Y4K3}. Lipid droplet
{ECO:0000250|UniProtKB:P70196}. Note=RSAD2/viperin recruits it to
the lipid droplet. {ECO:0000250|UniProtKB:P70196}.
-!- DOMAIN: The coiled coil domain mediates homo- and hetero-
oligomerization. {ECO:0000250|UniProtKB:Q9Y4K3}.
-!- DOMAIN: The MATH/TRAF domain binds to receptor cytoplasmic
domains. {ECO:0000250|UniProtKB:Q9Y4K3}.
-!- PTM: Sumoylated on Lys-124, Lys-142 and Lys-461 with SUMO1.
-!- PTM: Polyubiquitinated; after cell stimulation with IL-1-beta or
TGF-beta. This ligand-induced cell stimulation leads to
dimerization/oligomerization of TRAF6 molecules, followed by auto-
ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6
activation. This 'Lys-63' site-specific poly-ubiquitination
appears to be associated with the activation of signaling
molecules. Endogenous autoubiquitination occurs only for the
cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent
manner, leading to the negative regulation of NF-kappaB signaling
upon DNA damage. {ECO:0000250|UniProtKB:Q9Y4K3}.
-!- SIMILARITY: Belongs to the TNF receptor-associated factor family.
A subfamily. {ECO:0000305}.
Copyrighted by the UniProt Consortium, see
Distributed under the Creative Commons Attribution (CC BY 4.0) License
EMBL; CH473949; EDL79625.1; -; Genomic_DNA.
EMBL; BC168921; AAI68921.1; -; mRNA.
RefSeq; NP_001101224.1; NM_001107754.2.
SMR; B5DF45; -.
BioGrid; 259875; 9.
STRING; 10116.ENSRNOP00000006148; -.
PhosphoSitePlus; B5DF45; -.
PaxDb; B5DF45; -.
PeptideAtlas; B5DF45; -.
PRIDE; B5DF45; -.
Ensembl; ENSRNOT00000006148; ENSRNOP00000006148; ENSRNOG00000004639.
GeneID; 311245; -.
KEGG; rno:311245; -.
UCSC; RGD:1306853; rat.
CTD; 7189; -.
RGD; 1306853; Traf6.
eggNOG; ENOG410ISDW; Eukaryota.
GeneTree; ENSGT00940000155426; -.
HOGENOM; HOG000006625; -.
InParanoid; B5DF45; -.
KO; K03175; -.
OrthoDB; 918518at2759; -.
PhylomeDB; B5DF45; -.
TreeFam; TF321154; -.
Reactome; R-RNO-1257604; PIP3 activates AKT signaling.
Reactome; R-RNO-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
Reactome; R-RNO-168638; NOD1/2 Signaling Pathway.
Reactome; R-RNO-193692; Regulated proteolysis of p75NTR.
Reactome; R-RNO-202424; Downstream TCR signaling.
Reactome; R-RNO-205043; NRIF signals cell death from the nucleus.
Reactome; R-RNO-209543; p75NTR recruits signalling complexes.
Reactome; R-RNO-209560; NF-kB is activated and signals survival.
Reactome; R-RNO-2871837; FCERI mediated NF-kB activation.
Reactome; R-RNO-445989; TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
Reactome; R-RNO-450302; activated TAK1 mediates p38 MAPK activation.
Reactome; R-RNO-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
Reactome; R-RNO-5607764; CLEC7A (Dectin-1) signaling.
Reactome; R-RNO-5689880; Ub-specific processing proteases.
Reactome; R-RNO-5689896; Ovarian tumor domain proteases.
Reactome; R-RNO-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
Reactome; R-RNO-9020702; Interleukin-1 signaling.
Reactome; R-RNO-937039; IRAK1 recruits IKK complex.
Reactome; R-RNO-937042; IRAK2 mediated activation of TAK1 complex.
Reactome; R-RNO-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex.
Reactome; R-RNO-9645460; Alpha-protein kinase 1 signaling pathway.
Reactome; R-RNO-975110; TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling.
Reactome; R-RNO-975138; TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
Reactome; R-RNO-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
Reactome; R-RNO-975155; MyD88 dependent cascade initiated on endosome.
Reactome; R-RNO-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation.
Reactome; R-RNO-975871; MyD88 cascade initiated on plasma membrane.
UniPathway; UPA00143; -.
PRO; PR:B5DF45; -.
Proteomes; UP000002494; Chromosome 3.
Bgee; ENSRNOG00000004639; Expressed in 9 organ(s), highest expression level in liver.
Genevisible; B5DF45; RN.
GO; GO:0035631; C:CD40 receptor complex; IEA:Ensembl.
GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
GO; GO:0009898; C:cytoplasmic side of plasma membrane; IEA:Ensembl.
GO; GO:0005829; C:cytosol; IEA:Ensembl.
GO; GO:0005811; C:lipid droplet; ISS:UniProtKB.
GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
GO; GO:0032991; C:protein-containing complex; IDA:RGD.
GO; GO:0042826; F:histone deacetylase binding; IEA:Ensembl.
GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; IEA:Ensembl.
GO; GO:0043422; F:protein kinase B binding; IEA:Ensembl.
GO; GO:0047485; F:protein N-terminus binding; IEA:Ensembl.
GO; GO:0031996; F:thioesterase binding; IEA:Ensembl.
GO; GO:0005164; F:tumor necrosis factor receptor binding; IBA:GO_Central.
GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IEA:Ensembl.
GO; GO:0061630; F:ubiquitin protein ligase activity; IEA:Ensembl.
GO; GO:0031625; F:ubiquitin protein ligase binding; IEA:Ensembl.
GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IEA:Ensembl.
GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; IEA:Ensembl.
GO; GO:0045453; P:bone resorption; IEA:Ensembl.
GO; GO:0048468; P:cell development; IEA:Ensembl.
GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
GO; GO:0019221; P:cytokine-mediated signaling pathway; IMP:RGD.
GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IMP:RGD.
GO; GO:0007254; P:JNK cascade; IMP:RGD.
GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl.
GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
GO; GO:0001503; P:ossification; IEA:Ensembl.
GO; GO:0030316; P:osteoclast differentiation; IEA:Ensembl.
GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
GO; GO:0045084; P:positive regulation of interleukin-12 biosynthetic process; IEA:Ensembl.
GO; GO:0032743; P:positive regulation of interleukin-2 production; IEA:Ensembl.
GO; GO:0045410; P:positive regulation of interleukin-6 biosynthetic process; IEA:Ensembl.
GO; GO:0043507; P:positive regulation of JUN kinase activity; IEA:Ensembl.
GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IEA:Ensembl.
GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl.
GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IMP:RGD.
GO; GO:0002726; P:positive regulation of T cell cytokine production; IEA:Ensembl.
GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
GO; GO:2000679; P:positive regulation of transcription regulatory region DNA binding; IEA:Ensembl.
GO; GO:0051865; P:protein autoubiquitination; IEA:Ensembl.
GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
GO; GO:0051023; P:regulation of immunoglobulin secretion; IEA:Ensembl.
GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl.
GO; GO:0042088; P:T-helper 1 type immune response; IEA:Ensembl.
CDD; cd03776; MATH_TRAF6; 1.
Gene3D;; -; 1.
Gene3D;; -; 3.
InterPro; IPR002083; MATH/TRAF_dom.
InterPro; IPR012227; TNF_rcpt--assoc_TRAF.
InterPro; IPR008974; TRAF-like.
InterPro; IPR027139; TRAF6.
InterPro; IPR037309; TRAF6_MATH.
InterPro; IPR041310; TRAF6_Z2.
InterPro; IPR001841; Znf_RING.
InterPro; IPR013083; Znf_RING/FYVE/PHD.
InterPro; IPR017907; Znf_RING_CS.
InterPro; IPR001293; Znf_TRAF.
PANTHER; PTHR10131:SF131; PTHR10131:SF131; 1.
Pfam; PF18048; TRAF6_Z2; 1.
Pfam; PF02176; zf-TRAF; 1.
PIRSF; PIRSF015614; TRAF; 1.
SMART; SM00061; MATH; 1.
SMART; SM00184; RING; 1.
SUPFAM; SSF49599; SSF49599; 3.
PROSITE; PS50144; MATH; 1.
PROSITE; PS00518; ZF_RING_1; 1.
PROSITE; PS50089; ZF_RING_2; 1.
2: Evidence at transcript level;
Coiled coil; Complete proteome; Cytoplasm; DNA damage; Immunity;
Isopeptide bond; Lipid droplet; Metal-binding; Nucleus; Osteopetrosis;
Reference proteome; Repeat; Transferase; Ubl conjugation;
Ubl conjugation pathway; Zinc; Zinc-finger.
CHAIN 1 530 TNF receptor-associated factor 6.
DOMAIN 358 507 MATH. {ECO:0000255|PROSITE-
ZN_FING 70 109 RING-type; degenerate.
ZN_FING 150 202 TRAF-type 1. {ECO:0000255|PROSITE-
ZN_FING 203 259 TRAF-type 2. {ECO:0000255|PROSITE-
REGION 1 362 Interaction with TAX1BP1. {ECO:0000250}.
REGION 363 530 Interaction with TANK.
COILED 302 356 {ECO:0000255}.
CROSSLNK 124 124 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO);
alternate. {ECO:0000250}.
CROSSLNK 124 124 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in ubiquitin);
CROSSLNK 142 142 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO).
CROSSLNK 461 461 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO).

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