Homo sapiens Gene: TRAF6
Summary
InnateDB Gene IDBG-118973.1
Last Modified 2018-06-05 [Report errors or provide feedback]
Gene Symbol TRAF6
Gene Name TNF receptor associated factor 6
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.
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 549 experimentally validated interaction(s) in this database.
They are also associated with 132 interaction(s) predicted by orthology.
Experimentally validated
Total 549 [view]
Protein-Protein 536 [view]
Protein-DNA 4 [view]
Protein-RNA 0
DNA-DNA 7 [view]
RNA-RNA 2 [view]
DNA-RNA 0
Predicted by orthology
Total 132 [view]
Gene Ontology

Molecular Function
Accession GO Term
GO:0004842 ubiquitin-protein transferase activity
GO:0005164 tumor necrosis factor receptor binding
GO:0005515 protein binding
GO:0008270 zinc ion binding
GO:0016740 transferase 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:0042802 identical protein binding
GO:0042826 histone deacetylase binding
GO:0043422 protein kinase B binding
GO:0046872 metal ion binding
GO:0047485 protein N-terminus binding
GO:0061630 ubiquitin protein ligase activity
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:0002223 stimulatory C-type lectin receptor signaling pathway
GO:0002224 toll-like receptor signaling pathway
GO:0002376 immune system process
GO:0002726 positive regulation of T cell cytokine production
GO:0002755 MyD88-dependent toll-like receptor signaling pathway
GO:0006955 immune response
GO:0006974 cellular response to DNA damage stimulus
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 animal organ morphogenesis
GO:0016567 protein ubiquitination
GO:0016579 protein deubiquitination
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:0034162 toll-like receptor 9 signaling pathway
GO:0038095 Fc-epsilon receptor 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:0043122 regulation of I-kappaB kinase/NF-kappaB signaling
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: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:0048468 cell development
GO:0048661 positive regulation of smooth muscle cell proliferation
GO:0050852 T cell receptor signaling pathway
GO:0051023 regulation of immunoglobulin secretion
GO:0051091 positive regulation of DNA binding transcription factor activity
GO:0051092 positive regulation of NF-kappaB transcription factor activity
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:2000679 positive regulation of transcription regulatory region DNA binding
Cellular Component
GO:0005634 nucleus
GO:0005737 cytoplasm
GO:0005811 lipid droplet
GO:0005829 cytosol
GO:0005886 plasma membrane
GO:0005938 cell cortex
GO:0009898 cytoplasmic side of plasma membrane
GO:0010008 endosome membrane
GO:0032991 macromolecular complex
GO:0035631 CD40 receptor complex
GO:0048471 perinuclear region of cytoplasm
Orthologs
No orthologs found for this gene
Pathways
NETPATH
RANKL pathway
IL1 pathway
TCR pathway
TNFalpha pathway
TGF_beta_Receptor pathway
REACTOME
MyD88 dependent cascade initiated on endosome pathway
Toll Like Receptor 3 (TLR3) Cascade pathway
p75NTR recruits signalling complexes pathway
Death Receptor Signalling pathway
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation pathway
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling pathway
p75 NTR receptor-mediated signalling pathway
Post-translational protein modification pathway
Toll Like Receptor TLR1:TLR2 Cascade pathway
Toll Like Receptor 5 (TLR5) Cascade pathway
activated TAK1 mediates p38 MAPK activation pathway
Ovarian tumor domain proteases pathway
Regulated proteolysis of p75NTR pathway
FCERI mediated NF-kB activation pathway
Cell death signalling via NRAGE, NRIF and NADE pathway
Toll Like Receptor 2 (TLR2) Cascade pathway
Negative regulation of the PI3K/AKT network pathway
Toll-Like Receptors Cascades pathway
NF-kB is activated and signals survival pathway
Toll Like Receptor 4 (TLR4) Cascade pathway
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 pathway
IRAK1 recruits IKK complex pathway
Interleukin-17 signaling pathway
Ub-specific processing proteases pathway
Interleukin-1 family signaling pathway
p75NTR signals via NF-kB pathway
Signaling by Interleukins pathway
Signal Transduction pathway
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation pathway
Metabolism of proteins pathway
IRAK2 mediated activation of TAK1 complex pathway
IKK complex recruitment mediated by RIP1 pathway
Immune System pathway
NOD1/2 Signaling Pathway pathway
MAP kinase activation pathway
TCR signaling pathway
CLEC7A (Dectin-1) signaling pathway
Interleukin-1 signaling pathway
TRIF(TICAM1)-mediated TLR4 signaling pathway
Downstream TCR signaling pathway
TRAF6 mediated NF-kB activation pathway
TAK1 activates NFkB by phosphorylation and activation of IKKs complex pathway
Innate Immune System pathway
PIP3 activates AKT signaling pathway
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling pathway
MyD88 cascade initiated on plasma membrane pathway
DDX58/IFIH1-mediated induction of interferon-alpha/beta pathway
Toll Like Receptor 7/8 (TLR7/8) Cascade pathway
TICAM1, RIP1-mediated IKK complex recruitment pathway
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways pathway
MyD88-independent TLR4 cascade pathway
Toll Like Receptor 9 (TLR9) Cascade pathway
Toll Like Receptor TLR6:TLR2 Cascade pathway
TRAF6-mediated induction of TAK1 complex within TLR4 complex pathway
Cytokine Signaling in Immune system pathway
Adaptive Immune System pathway
Intracellular signaling by second messengers pathway
Toll Like Receptor 10 (TLR10) Cascade pathway
Deubiquitination pathway
NRIF signals cell death from the nucleus pathway
MyD88:Mal cascade initiated on plasma membrane pathway
TICAM1,TRAF6-dependent induction of TAK1 complex pathway
Fc epsilon receptor (FCERI) signaling pathway
C-type lectin receptors (CLRs) pathway
TRAF6 mediated IRF7 activation pathway
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation pathway
KEGG
MAPK signaling pathway pathway
NF-kappa B signaling pathway pathway
Ubiquitin mediated proteolysis pathway
Autophagy 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
IL-17 signaling pathway pathway
Neurotrophin signaling pathway pathway
Pertussis pathway
Leishmaniasis pathway
Chagas disease (American trypanosomiasis) pathway
Toxoplasmosis pathway
Tuberculosis pathway
Hepatitis C pathway
Measles pathway
Herpes simplex infection pathway
Epstein-Barr virus infection pathway
Pathways in cancer pathway
Small cell lung cancer pathway
INOH
B cell receptor signaling.owl pathway
TLR p38.owl pathway
IL-1 JNK.owl pathway
TLR ECSIT MEKK1 p38.owl pathway
TLR JNK.owl pathway
IL-1 p38.owl pathway
IL-1 NFkB.owl pathway
TLR ECSIT MEKK1 JNK.owl pathway
TLR NFkB.owl pathway
PID BIOCARTA
PID NCI
IL1-mediated signaling events
TCR signaling in nave CD4+ T cells
CD40/CD40L signaling
p75(NTR)-mediated signaling
Regulation of p38-alpha and p38-beta
BCR signaling pathway
TCR signaling in nave CD8+ T cells
Canonical NF-kappaB pathway
p38 MAPK signaling pathway
Cross-References
SwissProt Q9Y4K3
TrEMBL
UniProt Splice Variant
Entrez Gene 7189
UniGene
RefSeq NM_145803 NM_004620
HUGO HGNC:12036
OMIM 602355
CCDS CCDS7901
HPRD
IMGT
EMBL AC009656 AC061999 AK292978 AY228337 BC031052 CH471064 U78798
GenPept AAB38751 AAH31052 AAO38054 BAF85667 EAW68119 EAW68120 EAW68122
RNA Seq Atlas 7189