TRAF6_RAT
ID TRAF6_RAT Reviewed; 530 AA.
AC B5DF45;
DT 09-FEB-2010, integrated into UniProtKB/Swiss-Prot.
DT 14-OCT-2008, sequence version 1.
DT 03-AUG-2022, entry version 120.
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 Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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).
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-124, Lys-142 and Lys-461 with SUMO1.
CC {ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- PTM: Polyubiquitinated on Lys-124 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; CH473949; EDL79625.1; -; Genomic_DNA.
DR EMBL; BC168921; AAI68921.1; -; mRNA.
DR RefSeq; NP_001101224.1; NM_001107754.2.
DR AlphaFoldDB; B5DF45; -.
DR SMR; B5DF45; -.
DR BioGRID; 259875; 9.
DR STRING; 10116.ENSRNOP00000006148; -.
DR PhosphoSitePlus; B5DF45; -.
DR PaxDb; B5DF45; -.
DR PeptideAtlas; B5DF45; -.
DR PRIDE; B5DF45; -.
DR Ensembl; ENSRNOT00000006148; ENSRNOP00000006148; ENSRNOG00000004639.
DR GeneID; 311245; -.
DR KEGG; rno:311245; -.
DR UCSC; RGD:1306853; rat.
DR CTD; 7189; -.
DR RGD; 1306853; Traf6.
DR eggNOG; KOG0297; Eukaryota.
DR GeneTree; ENSGT00940000155426; -.
DR HOGENOM; CLU_021061_5_0_1; -.
DR InParanoid; B5DF45; -.
DR OMA; WMQKNNQ; -.
DR OrthoDB; 918518at2759; -.
DR PhylomeDB; B5DF45; -.
DR TreeFam; TF321154; -.
DR Reactome; R-RNO-1257604; PIP3 activates AKT signaling.
DR Reactome; R-RNO-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR Reactome; R-RNO-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-RNO-202424; Downstream TCR signaling.
DR Reactome; R-RNO-205043; NRIF signals cell death from the nucleus.
DR Reactome; R-RNO-209543; p75NTR recruits signalling complexes.
DR Reactome; R-RNO-209560; NF-kB is activated and signals survival.
DR Reactome; R-RNO-2871837; FCERI mediated NF-kB activation.
DR Reactome; R-RNO-450302; activated TAK1 mediates p38 MAPK activation.
DR Reactome; R-RNO-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
DR Reactome; R-RNO-5607764; CLEC7A (Dectin-1) signaling.
DR Reactome; R-RNO-5689880; Ub-specific processing proteases.
DR Reactome; R-RNO-5689896; Ovarian tumor domain proteases.
DR Reactome; R-RNO-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-RNO-9020702; Interleukin-1 signaling.
DR Reactome; R-RNO-937039; IRAK1 recruits IKK complex.
DR Reactome; R-RNO-937042; IRAK2 mediated activation of TAK1 complex.
DR Reactome; R-RNO-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex.
DR Reactome; R-RNO-9645460; Alpha-protein kinase 1 signaling pathway.
DR Reactome; R-RNO-975138; TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
DR Reactome; R-RNO-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
DR Reactome; R-RNO-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation.
DR Reactome; R-RNO-975871; MyD88 cascade initiated on plasma membrane.
DR UniPathway; UPA00143; -.
DR PRO; PR:B5DF45; -.
DR Proteomes; UP000002494; Chromosome 3.
DR Proteomes; UP000234681; Chromosome 3.
DR Bgee; ENSRNOG00000004639; Expressed in jejunum and 18 other tissues.
DR Genevisible; B5DF45; RN.
DR GO; GO:0035631; C:CD40 receptor complex; ISO:RGD.
DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISO:RGD.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0005811; C:lipid droplet; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISO:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0032991; C:protein-containing complex; IDA:RGD.
DR GO; GO:0042826; F:histone deacetylase binding; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; ISO:RGD.
DR GO; GO:0043422; F:protein kinase B binding; ISO:RGD.
DR GO; GO:0019901; F:protein kinase binding; ISO:RGD.
DR GO; GO:0047485; F:protein N-terminus binding; ISO:RGD.
DR GO; GO:0031996; F:thioesterase binding; ISO:RGD.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; ISO:RGD.
DR GO; GO:0032813; F:tumor necrosis factor receptor superfamily binding; IBA:GO_Central.
DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; ISO:RGD.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISO:RGD.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0032147; P:activation of protein kinase activity; ISO:RGD.
DR GO; GO:0009887; P:animal organ morphogenesis; ISO:RGD.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; ISO:RGD.
DR GO; GO:0046849; P:bone remodeling; ISO:RGD.
DR GO; GO:0045453; P:bone resorption; ISO:RGD.
DR GO; GO:0048468; P:cell development; ISO:RGD.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISO:RGD.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISO:RGD.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IMP:RGD.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; ISO:RGD.
DR GO; GO:0006955; P:immune response; ISO:RGD.
DR GO; GO:0001701; P:in utero embryonic development; ISO:RGD.
DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IMP:RGD.
DR GO; GO:0097400; P:interleukin-17-mediated signaling pathway; ISO:RGD.
DR GO; GO:0007254; P:JNK cascade; IMP:RGD.
DR GO; GO:0043011; P:myeloid dendritic cell differentiation; ISO:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0001843; P:neural tube closure; ISO:RGD.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; ISO:RGD.
DR GO; GO:0001503; P:ossification; ISO:RGD.
DR GO; GO:0030316; P:osteoclast differentiation; ISO:RGD.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0032743; P:positive regulation of interleukin-2 production; ISO:RGD.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISO:RGD.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IBA:GO_Central.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; ISO:RGD.
DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; ISO:RGD.
DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; ISO:RGD.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IMP:RGD.
DR GO; GO:0002726; P:positive regulation of T cell cytokine production; ISO:RGD.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:2000679; P:positive regulation of transcription regulatory region DNA binding; ISO:RGD.
DR GO; GO:0051865; P:protein autoubiquitination; ISO:RGD.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; ISO:RGD.
DR GO; GO:0016567; P:protein ubiquitination; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0070555; P:response to interleukin-1; ISO:RGD.
DR GO; GO:0002931; P:response to ischemia; IEP:RGD.
DR GO; GO:0007165; P:signal transduction; ISO:RGD.
DR GO; GO:0050852; P:T cell receptor signaling pathway; ISO:RGD.
DR GO; GO:0042088; P:T-helper 1 type immune response; ISO:RGD.
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..530
FT /note="TNF receptor-associated factor 6"
FT /id="PRO_0000391611"
FT DOMAIN 358..507
FT /note="MATH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00129"
FT ZN_FING 70..109
FT /note="RING-type; degenerate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 150..202
FT /note="TRAF-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT ZN_FING 203..259
FT /note="TRAF-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT REGION 1..362
FT /note="Interaction with TAX1BP1"
FT /evidence="ECO:0000250"
FT REGION 363..530
FT /note="Interaction with TANK"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3"
FT COILED 302..356
FT /evidence="ECO:0000255"
FT CROSSLNK 124
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250"
FT CROSSLNK 124
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3"
FT CROSSLNK 142
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT CROSSLNK 461
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
SQ SEQUENCE 530 AA; 60253 MW; 5DCC4DEB4CF2DA4F CRC64;
MSLLNCENSC ASSQSSSDCC AAMANSCSAA MKDDSVSGCV STGNLSSSFM EEIQGYDVEF
DPPLESKYEC PICLMALREA VQTPCGHRFC KACITKSIRD AGHKCPVDNE ILLENQLFPD
NFAKREILSL TVKCPNKGCV QKMELRHLED HQVHCEFALV ICPQCQRFFQ KCQINKHIIE
DCPRRQVSCV NCAVPMPYEE KEIHDQSCPL ANIICEYCGT ILIREQMPNH YDLDCPTAPV
PCTFSVFGCH EKMQRNHLAR HLQENTQLHM RLLAQAVHNV NLSLRPCDAS SPSRGCRPED
PNYEETVKQL EGRLVRQDHQ IRELTAKMET QSMHVSELKR TIRSLEDKVA EMEAQQCNGI
YIWKIGNFGM HLKSQEEERP VVIHSPGFYT GRPGYKLCMR LHLQLPTAQR CANYISLFVH
TMQGEYDSHL PWPFQGTIRL TILDQSEAVI RQNHEEVMDA KPELLAFQRP TIPRNPKGFG
YVTFMHLEAL RQGTFIKDDT LLVRCEVSTR FDMGGLRKEG FQPRSTDAGV
