Homo sapiens Gene: TRAF6
Summary
InnateDB Gene IDBG-40102.7
Last Modified 2014-10-13 [Report errors or provide feedback]
Gene Symbol TRAF6
Gene Name TNF receptor-associated factor 6, E3 ubiquitin protein ligase
Synonyms MGC:3310; RNF85;
Species Homo sapiens
Ensembl Gene ENSG00000175104
Encoded Proteins
TNF receptor-associated factor 6
TNF receptor-associated factor 6
Protein Structure
Useful resources Stemformatics EHFPI ImmGen
InnateDB Annotation
Summary
TRAF6 is an adapter protein linking kinases to TNF receptor, and IL-1 receptor signalling pathways, and also has E3 ubiquitin ligase activity.
TRAF6 autoubiquitination and its interaction with Ubc13 are dependent on zinc finger 1 (ZF1) motif and an intact RING domain, necessary elements in signalling by IL-1, LPS and RANKL.
TRAF6 is specifically required for the Smad-independent activation of JNK and p38, and its carboxyl TRAF homology domain physically interacts with TGF-beta receptors that activate JNK and p38 through a mechanism similar to that operating in the interleukin-1beta/Toll-like receptor pathway.
TRAF6 and MEK kinase 1 (MEKK1) play a pivotal role in the retinoic-acid-inducible gene-I (RIG-I)-like helicase antiviral pathway, where TRAF6 and MEKK1 activate NF-kappaB and mitogen-activated protein kinases via MAVS and this is critical for the optimal induction of type I interferons.
TRAF6 negatively regulates TNFalpha-induced NF-kappaB activation through its ubiquitin ligase activity.
TRAF6 regulates several signalling cascades in innate immunity, adaptive immunity and bone homeostasis.
TRAF6 competes with TRAF2 for CD40 binding to regulate NF-kappaB activation in human B lymphocytes, thereby limiting the capacity of CD40 engagement to induce NF-kappaB activation.
TRAF6 is autoinhibited by an intramolecular interaction which is counteracted by trans-ubiquitination and TRAF auto-ubiquitination is a means of sustaining an open conformation active in downstream signalling.
TRAF6 interacts with CSF2RB to mediate NF-kappaB signalling, demonstrating a novel TRAF6-dependent signalling pathway association with a type I cytokine receptor.
TRAF6 is a E3 ubiquitin ligase that activates NFKB pathway in response to innate and adaptive immunity stimuli. TRAF6 protein contains a highly conserved TRAF-C domain that contributes to oligomerization and its interaction to upstream signalling molecules and a RING domain dimerization interface that is functionally important for ubiquitination and the activation of NFKB.
TRAF6 is polyubiquitinated and disassembled during endotoxin tolerization; a process which impairs the production of LPS-induced pro-inflammatory cytokines without inhibition expression of anti-inflammatory or anti-microbial mediators.
TRAF6 is degraded in the proteasome upon TLR stimulation in macrophages. (Demonstrated in mice)
Following NOD2 activation, IRF4 interacts with MYD88, TRAF6, and RIPK2 and downregulates K63-linked polyubiquitinylation of RICK and TRAF6 leading to disruption of NFkB activation pathways.
MIR146A is a potent negative regulator of the innate immune response in keratinocytes through downregulation of the IRAK1/TRAF6/NFκB pathway.
STAT1 is directly recruited to TRAF6, demonstrating cross-talk between the TLR and JAK/STAT signalling pathways, and this direct activation of STAT1 by TLR signalling suggests a crucial role for STAT1 in TLR-induced inflammation. Demonstrated in mice.
ECSIT binds to MAP3K7 and TRAF6 to form a complex that plays a pivotal role in activating TLR4-mediated NF-kB signalling.
Reversible arginine methylation of TRAF6 is regulated by PRMT1 and JMJD6 and this in turn regulates TRAF6-dependent TLR signalling.
MAVS directly interacts with TRAF6 through its potential TRAF6-binding motif 2.
InnateDB Annotation from Orthologs
Summary
[Mus musculus] Traf6 is a E3 ubiquitin ligase that activates NFKB pathway in response to innate and adaptive immunity stimuli. Traf6 protein contains a highly conserved TRAF-C domain that contributes to oligomerization and its interaction to upstream signalling molecules, and a RING domain dimerization interface that is functionally important for ubiquitination and the activation of NFKB.
[Mus musculus] Traf6 is polyubiquitinated and disassembled during endotoxin tolerization; a process which impairs the production of LPS-induced pro-inflammatory cytokines without inhibition expression of anti-inflammatory or anti-microbial mediators.
[Mus musculus] Traf6 is degraded in the proteasome upon TLR stimulation in macrophages.
[Mus musculus] The binding of MAVS to Traf2, Traf5, and Traf6 is dependent on virus infection and MAVS polymerization. The TRAF proteins promote ubiquitination that recruits IKBKG binding to the MAVS signalling complex.
[Mus musculus] Mir146 attenuates sepsis-induced cardiac dysfunction by preventing NFκB activation, inflammatory cell infiltration, and inflammatory cytokine production via targeting of Irak1 and Traf6 in both cardiomyocytes and inflammatory monocytic cells
[Mus musculus] Intracellular Sef/IL-17R (SEFIR) domain of Il17rd targets TIR adaptor proteins Myd88, Tirap, Ticam1, Ticam2 and Traf6 to inhibit TLR downstream signalling.
[Mus musculus] Trim12c interacts with Traf6, a key protein in pathogen recognition receptor signalling, and reciprocally enhances its ubiquitination, leading to cooperative activation of IFN and NF-kB pathways.
[Mus musculus] Usp25 physically associates with Traf3 and Traf6 after infection by RNA or DNA viruses and promotes innate antiviral responses by protecting virus-induced proteasome-dependent or independent degradation of Traf3 and Traf6.
Entrez Gene
Summary The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from, members of the TNF receptor superfamily. This protein mediates signaling from members of the TNF receptor superfamily as well as the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/RANCE and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including IRAK1/IRAK, SRC and PKCzeta, which provides a link between distinct signaling pathways. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. This protein also interacts with the transforming growth factor (TGF) beta receptor complex and is required for Smad-independent activation of the JNK and p38 kinases. This protein has an amino terminal RING domain which is followed by four zinc-finger motifs, a central coiled-coil region and a highly conserved carboxyl terminal domain, known as the TRAF-C domain. Two alternatively spliced transcript variants, encoding an identical protein, have been reported. [provided by RefSeq, Feb 2012]
Gene Information
Type Protein coding
Genomic Location Chromosome 11:36487027-36510272
Strand Reverse strand
Band p12
Transcripts
ENST00000348124 ENSP00000337853
ENST00000526995 ENSP00000433623
ENST00000529150
Interactions
Number of Interactions This gene and/or its encoded proteins are associated with 398 experimentally validated interaction(s) in this database.
They are also associated with 95 interaction(s) predicted by orthology.
Experimentally validated
Total 398 [view]
Protein-Protein 387 [view]
Protein-DNA 3 [view]
Protein-RNA 0
DNA-DNA 6 [view]
RNA-RNA 2 [view]
DNA-RNA 0
Predicted by orthology
Total 95 [view]
Gene Ontology

Molecular Function
Accession GO Term
GO:0004842 ubiquitin-protein transferase activity
GO:0004871 signal transducer activity
GO:0005164 tumor necrosis factor receptor binding
GO:0005515 protein binding
GO:0008270 zinc ion binding
GO:0016874 ligase activity
GO:0019901 protein kinase binding
GO:0031435 mitogen-activated protein kinase kinase kinase binding
GO:0031624 ubiquitin conjugating enzyme binding
GO:0031625 ubiquitin protein ligase binding
GO:0031996 thioesterase binding
GO:0042826 histone deacetylase binding
GO:0043422 protein kinase B binding
GO:0046872 metal ion binding
GO:0047485 protein N-terminus binding
Biological Process
GO:0000122 negative regulation of transcription from RNA polymerase II promoter
GO:0000187 activation of MAPK activity
GO:0000209 protein polyubiquitination
GO:0001503 ossification
GO:0001843 neural tube closure
GO:0002224 toll-like receptor signaling pathway
GO:0002726 positive regulation of T cell cytokine production
GO:0002755 MyD88-dependent toll-like receptor signaling pathway
GO:0002756 MyD88-independent toll-like receptor signaling pathway
GO:0006461 protein complex assembly
GO:0006955 immune response
GO:0007165 signal transduction
GO:0007249 I-kappaB kinase/NF-kappaB signaling
GO:0007250 activation of NF-kappaB-inducing kinase activity
GO:0007254 JNK cascade
GO:0009887 organ morphogenesis
GO:0016567 protein ubiquitination
GO:0019221 cytokine-mediated signaling pathway
GO:0019886 antigen processing and presentation of exogenous peptide antigen via MHC class II
GO:0030316 osteoclast differentiation
GO:0031293 membrane protein intracellular domain proteolysis
GO:0031398 positive regulation of protein ubiquitination
GO:0031666 positive regulation of lipopolysaccharide-mediated signaling pathway
GO:0032147 activation of protein kinase activity
GO:0032743 positive regulation of interleukin-2 production
GO:0034134 toll-like receptor 2 signaling pathway
GO:0034138 toll-like receptor 3 signaling pathway
GO:0034142 toll-like receptor 4 signaling pathway
GO:0034146 toll-like receptor 5 signaling pathway
GO:0034162 toll-like receptor 9 signaling pathway
GO:0034166 toll-like receptor 10 signaling pathway
GO:0035666 TRIF-dependent toll-like receptor signaling pathway
GO:0035872 nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
GO:0038095 Fc-epsilon receptor signaling pathway
GO:0038123 toll-like receptor TLR1:TLR2 signaling pathway
GO:0038124 toll-like receptor TLR6:TLR2 signaling pathway
GO:0042088 T-helper 1 type immune response
GO:0042102 positive regulation of T cell proliferation
GO:0042475 odontogenesis of dentin-containing tooth
GO:0042981 regulation of apoptotic process
GO:0043011 myeloid dendritic cell differentiation
GO:0043065 positive regulation of apoptotic process
GO:0043066 negative regulation of apoptotic process
GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043507 positive regulation of JUN kinase activity
GO:0045084 positive regulation of interleukin-12 biosynthetic process
GO:0045087 innate immune response (InnateDB)
GO:0045410 positive regulation of interleukin-6 biosynthetic process
GO:0045453 bone resorption
GO:0045672 positive regulation of osteoclast differentiation
GO:0045892 negative regulation of transcription, DNA-templated
GO:0045944 positive regulation of transcription from RNA polymerase II promoter
GO:0046849 bone remodeling
GO:0048011 neurotrophin TRK receptor signaling pathway
GO:0048468 cell development
GO:0048661 positive regulation of smooth muscle cell proliferation
GO:0050852 T cell receptor signaling pathway
GO:0050870 positive regulation of T cell activation
GO:0051023 regulation of immunoglobulin secretion
GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity
GO:0051092 positive regulation of NF-kappaB transcription factor activity
GO:0051403 stress-activated MAPK cascade
GO:0051865 protein autoubiquitination
GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway
GO:0070498 interleukin-1-mediated signaling pathway
GO:0070534 protein K63-linked ubiquitination
GO:0070555 response to interleukin-1
GO:0071222 cellular response to lipopolysaccharide
GO:0097190 apoptotic signaling pathway
GO:2000679 positive regulation of transcription regulatory region DNA binding
Cellular Component
GO:0005634 nucleus
GO:0005730 nucleolus
GO:0005737 cytoplasm
GO:0005739 mitochondrion
GO:0005811 lipid particle
GO:0005829 cytosol
GO:0005886 plasma membrane
GO:0005938 cell cortex
GO:0009898 cytoplasmic side of plasma membrane
GO:0010008 endosome membrane
GO:0035631 CD40 receptor complex
GO:0043234 protein complex
GO:0048471 perinuclear region of cytoplasm
Orthologs
Species
Mus musculus
Bos taurus
Gene ID
Gene Order
Method
Confidence
Comments
SSD Ortholog
Ortholog supports species divergence
Not yet available
SSD Ortholog
Ortholog supports species divergence
Pathways
NETPATH
TGF_beta_Receptor pathway
TNFalpha pathway
TCR pathway
IL1 pathway
RANKL pathway
REACTOME
MyD88 dependent cascade initiated on endosome pathway
FCERI mediated NF-kB activation pathway
Signalling by NGF pathway
Toll Like Receptor 7/8 (TLR7/8) Cascade pathway
p75NTR recruits signalling complexes pathway
Toll Like Receptor TLR1:TLR2 Cascade pathway
Toll Like Receptor 9 (TLR9) Cascade pathway
Toll Like Receptor TLR6:TLR2 Cascade pathway
TCR signaling pathway
MyD88 cascade initiated on plasma membrane pathway
Cytokine Signaling in Immune system pathway
Innate Immune System pathway
NF-kB is activated and signals survival pathway
IKK complex recruitment mediated by RIP1 pathway
IRAK1 recruits IKK complex pathway
Toll Like Receptor 3 (TLR3) Cascade pathway
Toll Like Receptor 2 (TLR2) Cascade pathway
TRAF6 mediated IRF7 activation pathway
Toll-Like Receptors Cascades pathway
TRAF6 mediated NF-kB activation pathway
Fc epsilon receptor (FCERI) signaling pathway
p75 NTR receptor-mediated signalling pathway
p75NTR signals via NF-kB pathway
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways pathway
Signal Transduction pathway
TRAF6 mediated induction of TAK1 complex pathway
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation pathway
Regulated proteolysis of p75NTR pathway
MAP kinase activation in TLR cascade pathway
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways pathway
Adaptive Immune System pathway
NOD1/2 Signaling Pathway pathway
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation pathway
Immune System pathway
MyD88-independent cascade pathway
MyD88:Mal cascade initiated on plasma membrane pathway
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 pathway
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling pathway
NRIF signals cell death from the nucleus pathway
Signaling by Interleukins pathway
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation pathway
Downstream TCR signaling pathway
Interleukin-1 signaling pathway
Cell death signalling via NRAGE, NRIF and NADE pathway
Toll Like Receptor 4 (TLR4) Cascade pathway
Activated TLR4 signalling pathway
activated TAK1 mediates p38 MAPK activation pathway
IRAK2 mediated activation of TAK1 complex pathway
TRIF-mediated TLR3/TLR4 signaling pathway
Toll Like Receptor 5 (TLR5) Cascade pathway
TAK1 activates NFkB by phosphorylation and activation of IKKs complex pathway
Toll Like Receptor 10 (TLR10) Cascade pathway
KEGG
MAPK signaling pathway pathway
Ubiquitin mediated proteolysis pathway
Endocytosis pathway
Osteoclast differentiation pathway
Toll-like receptor signaling pathway pathway
NOD-like receptor signaling pathway pathway
RIG-I-like receptor signaling pathway pathway
Neurotrophin signaling pathway pathway
Leishmaniasis pathway
Chagas disease (American trypanosomiasis) pathway
Toxoplasmosis pathway
Hepatitis C pathway
Pathways in cancer pathway
Small cell lung cancer pathway
INOH
CD4 T cell receptor signaling pathway
IL-1 signaling pathway pathway
Toll-like receptor signaling pathway pathway
B cell receptor signaling pathway
PID BIOCARTA
Toll-like receptor pathway [Biocarta view]
Nf-kb signaling pathway [Biocarta view]
Bone remodeling [Biocarta view]
Signal transduction through il1r [Biocarta view]
Cd40l signaling pathway [Biocarta view]
Yaci and bcma stimulation of b cell immune responses [Biocarta view]
PID NCI
CD40/CD40L signaling
TCR signaling in nave CD8+ T cells
TCR signaling in nave CD4+ T cells
IL1-mediated signaling events
p75(NTR)-mediated signaling
BCR signaling pathway
Canonical NF-kappaB pathway
Regulation of p38-alpha and p38-beta
p38 MAPK signaling pathway
Cross-References
SwissProt
TrEMBL
UniProt Splice Variant
Entrez Gene
UniGene Hs.444172
RefSeq NM_004620 NM_145803
HUGO
OMIM
CCDS CCDS7901
HPRD 03833
IMGT
EMBL
GenPept
RNA Seq Atlas