Version 5.4
Mus musculus Gene: Traf6
Summary
InnateDB Gene IDBG-193222.6
Last Modified 2014-10-13 [Report errors or provide feedback]
Gene Symbol Traf6
Gene Name TNF receptor-associated factor 6
Synonyms 2310003F17Rik; AI851288; C630032O20Rik
Species Mus musculus
Ensembl Gene ENSMUSG00000027164
Encoded Proteins
IDBP-193224
TNF receptor-associated factor 6
Protein Structure
Useful resources Stemformatics EHFPI ImmGen
InnateDB Annotation
Summary
PMID 21185369
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.
PMID 21220427
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.
PMID 22033459
Traf6 is degraded in the proteasome upon TLR stimulation in macrophages.
PMID 23951545
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.
PMID 26048146
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
PMID 25808990
Intracellular Sef/IL-17R (SEFIR) domain of Il17rd targets TIR adaptor proteins Myd88, Tirap, Ticam1, Ticam2 and Traf6 to inhibit TLR downstream signalling.
PMID 26503954
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.
PMID 26305951
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.
InnateDB Annotation from Orthologs
Summary
PMID 16184196
[Homo sapiens] TRAF6 is an adapter protein linking kinases to TNF receptor, and IL-1 receptor signalling pathways, and also has E3 ubiquitin ligase activity.
PMID 18617513
[Homo sapiens] 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.
PMID 18922473
[Homo sapiens] 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.
PMID 18984593
[Homo sapiens] 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.
PMID 19091594
[Homo sapiens] TRAF6 negatively regulates TNFalpha-induced NF-kappaB activation through its ubiquitin ligase activity.
PMID 12140561
[Homo sapiens] TRAF6 regulates several signalling cascades in innate immunity, adaptive immunity and bone homeostasis.
PMID 20449947
[Homo sapiens] 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.
PMID 20512936
[Homo sapiens] 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.
PMID 20622119
[Homo sapiens] TRAF6 interacts with CSF2RB to mediate NF-kappaB signalling, demonstrating a novel TRAF6-dependent signalling pathway association with a type I cytokine receptor.
PMID 21185369
[Homo sapiens] 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.
PMID 21220427
[Homo sapiens] 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.
PMID 22033459
[Homo sapiens] TRAF6 is degraded in the proteasome upon TLR stimulation in macrophages. (Demonstrated in mice)
PMID 24670424
[Homo sapiens] 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.
PMID 24670381
[Homo sapiens] MIR146A is a potent negative regulator of the innate immune response in keratinocytes through downregulation of the IRAK1/TRAF6/NFκB pathway.
PMID 25027037
[Homo sapiens] 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.
PMID 25371197
[Homo sapiens] ECSIT binds to MAP3K7 and TRAF6 to form a complex that plays a pivotal role in activating TLR4-mediated NF-kB signalling.
PMID 26221041
[Homo sapiens] Reversible arginine methylation of TRAF6 is regulated by PRMT1 and JMJD6 and this in turn regulates TRAF6-dependent TLR signalling.
PMID 26385923
[Homo sapiens] MAVS directly interacts with TRAF6 through its potential TRAF6-binding motif 2.
Entrez Gene
Summary This gene does not have any Entrez summary - the following is the summary from its human ortholog ENSG00000175104:
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 2:101678429-101701669
Strand Forward strand
Band E2
Transcripts
ENSMUST00000004949 ENSMUSP00000004949
ENSMUST00000143341
ENSMUST00000144063
Interactions
Number of Interactions This gene and/or its encoded proteins are associated with 161 experimentally validated interaction(s) in this database.
They are also associated with 476 interaction(s) predicted by orthology.
Experimentally validated
Total 161 [view]
Protein-Protein 160 [view]
Protein-DNA 0
Protein-RNA 0
DNA-DNA 1 [view]
RNA-RNA 0
DNA-RNA 0
Predicted by orthology
Total 476 [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:0000209 protein polyubiquitination
GO:0001503 ossification
GO:0001843 neural tube closure
GO:0002726 positive regulation of T cell cytokine production
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:0031666 positive regulation of lipopolysaccharide-mediated signaling pathway
GO:0032147 activation of protein kinase activity
GO:0032743 positive regulation of interleukin-2 production
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: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: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 sequence-specific DNA binding transcription factor activity
GO:0051092 positive regulation of NF-kappaB transcription factor activity
GO:0051865 protein autoubiquitination
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: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:0031965 nuclear membrane
GO:0035631 CD40 receptor complex
GO:0043234 protein complex
GO:0048471 perinuclear region of cytoplasm
Orthologs
Species
Homo sapiens
Bos taurus
Gene ID
Gene Order
ENSG00000175104
View Gene Order
ENSBTAG00000036009
Not yet available
Pathways
NETPATH
REACTOME
REACT_202898
TRAF6 mediated NF-kB activation pathway
REACT_239142
Innate Immune System pathway
REACT_230745
Immune System pathway
REACT_219118
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways pathway
KEGG
mmu04120
Ubiquitin mediated proteolysis pathway
mmu04620
Toll-like receptor signaling pathway pathway
mmu04010
MAPK signaling pathway pathway
mmu05222
Small cell lung cancer pathway
mmu04722
Neurotrophin signaling pathway pathway
mmu04144
Endocytosis pathway
mmu05200
Pathways in cancer pathway
mmu04622
RIG-I-like receptor signaling pathway pathway
mmu04621
NOD-like receptor signaling pathway pathway
mmu05140
Leishmaniasis pathway
mmu04380
Osteoclast differentiation pathway
mmu05145
Toxoplasmosis pathway
mmu05160
Hepatitis C pathway
mmu05142
Chagas disease (American trypanosomiasis) pathway
INOH
INOH website
CD4 T cell receptor signaling pathway
INOH website
IL-1 signaling pathway pathway
INOH website
Toll-like receptor signaling pathway pathway
INOH website
B cell receptor signaling pathway
PID NCI
Pathway Predictions based on Human Orthology Data
NETPATH
NetPath_7
TGF_beta_Receptor pathway
NetPath_9
TNFalpha pathway
NetPath_11
TCR pathway
NetPath_13
IL1 pathway
NetPath_21
RANKL pathway
REACTOME
REACT_24938
TRAF6 mediated IRF7 activation pathway
REACT_24969
TRAF6 mediated NF-kB activation pathway
REACT_25359
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways pathway
REACT_21368
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 pathway
REACT_21399
activated TAK1 mediates p38 MAPK activation pathway
REACT_25351
TRAF6 mediated induction of TAK1 complex pathway
REACT_25374
IKK complex recruitment mediated by RIP1 pathway
REACT_21281
TAK1 activates NFkB by phosphorylation and activation of IKKs complex pathway
REACT_6809
MyD88-independent cascade pathway
REACT_6783
Toll Like Receptor 3 (TLR3) Cascade pathway
REACT_24918
IRAK1 recruits IKK complex pathway
REACT_25380
IRAK2 mediated activation of TAK1 complex pathway
REACT_6788
MyD88:Mal cascade initiated on plasma membrane pathway
REACT_8005
Toll Like Receptor TLR1:TLR2 Cascade pathway
REACT_8006
Toll Like Receptor TLR6:TLR2 Cascade pathway
REACT_25120
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling pathway
REACT_25018
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation pathway
REACT_25354
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation pathway
REACT_25024
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation pathway
REACT_25222
MyD88 dependent cascade initiated on endosome pathway
REACT_9047
Toll Like Receptor 9 (TLR9) Cascade pathway
REACT_27215
MyD88 cascade initiated on plasma membrane pathway
REACT_9027
Toll Like Receptor 10 (TLR10) Cascade pathway
REACT_6894
Toll Like Receptor 4 (TLR4) Cascade pathway
REACT_9061
Toll Like Receptor 5 (TLR5) Cascade pathway
REACT_75776
NOD1/2 Signaling Pathway pathway
REACT_12555
Downstream TCR signaling pathway
REACT_22442
Interleukin-1 signaling pathway
REACT_13443
Regulated proteolysis of p75NTR pathway
REACT_13415
p75NTR recruits signalling complexes pathway
REACT_13696
NF-kB is activated and signals survival pathway
REACT_13643
NRIF signals cell death from the nucleus pathway
REACT_163994
FCERI mediated NF-kB activation pathway
REACT_11061
Signalling by NGF pathway
REACT_9020
Toll Like Receptor 7/8 (TLR7/8) Cascade pathway
REACT_12526
TCR signaling pathway
REACT_75790
Cytokine Signaling in Immune system pathway
REACT_6802
Innate Immune System pathway
REACT_7980
Toll Like Receptor 2 (TLR2) Cascade pathway
REACT_6966
Toll-Like Receptors Cascades pathway
REACT_163936
Fc epsilon receptor (FCERI) signaling pathway
REACT_13776
p75 NTR receptor-mediated signalling pathway
REACT_13537
p75NTR signals via NF-kB pathway
REACT_111102
Signal Transduction pathway
REACT_21308
MAP kinase activation in TLR cascade pathway
REACT_75913
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways pathway
REACT_75774
Adaptive Immune System pathway
REACT_6900
Immune System pathway
REACT_22232
Signaling by Interleukins pathway
REACT_13720
Cell death signalling via NRAGE, NRIF and NADE pathway
REACT_6890
Activated TLR4 signalling pathway
REACT_25281
TRIF-mediated TLR3/TLR4 signaling pathway
REACT_224941
NOD1/2 Signaling Pathway pathway
REACT_218237
Toll Like Receptor 2 (TLR2) Cascade pathway
REACT_210286
TRIF-mediated TLR3/TLR4 signaling pathway
REACT_222410
IRAK2 mediated activation of TAK1 complex pathway
REACT_224703
Toll Like Receptor 3 (TLR3) Cascade pathway
REACT_205566
Activated TLR4 signalling pathway
REACT_222278
Toll Like Receptor 7/8 (TLR7/8) Cascade pathway
REACT_224546
MyD88-independent cascade pathway
REACT_207897
activated TAK1 mediates p38 MAPK activation pathway
REACT_217035
Toll Like Receptor 9 (TLR9) Cascade pathway
REACT_221101
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways pathway
REACT_227345
MyD88:Mal cascade initiated on plasma membrane pathway
REACT_210227
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling pathway
REACT_210224
Toll Like Receptor 5 (TLR5) Cascade pathway
REACT_213612
Cytokine Signaling in Immune system pathway
REACT_205423
Downstream TCR signaling pathway
REACT_226623
NRIF signals cell death from the nucleus pathway
REACT_213138
Immune System pathway
REACT_227036
MAP kinase activation in TLR cascade pathway
REACT_211402
Cell death signalling via NRAGE, NRIF and NADE pathway
REACT_211964
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 pathway
REACT_219220
Toll-Like Receptors Cascades pathway
REACT_214353
Signal Transduction pathway
REACT_207058
TRAF6 mediated NF-kB activation pathway
REACT_221145
NF-kB is activated and signals survival pathway
REACT_219947
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways pathway
REACT_223848
Toll Like Receptor 10 (TLR10) Cascade pathway
REACT_225653
Toll Like Receptor TLR6:TLR2 Cascade pathway
REACT_218091
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation pathway
REACT_227494
p75NTR recruits signalling complexes pathway
REACT_207066
Signalling by NGF pathway
REACT_219042
FCERI mediated NF-kB activation pathway
REACT_227790
Regulated proteolysis of p75NTR pathway
REACT_214519
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation pathway
REACT_227483
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation pathway
REACT_214469
Adaptive Immune System pathway
REACT_216676
Toll Like Receptor TLR1:TLR2 Cascade pathway
REACT_219586
MyD88 dependent cascade initiated on endosome pathway
REACT_217214
TAK1 activates NFkB by phosphorylation and activation of IKKs complex pathway
REACT_218986
TRAF6 mediated IRF7 activation pathway
REACT_218183
p75 NTR receptor-mediated signalling pathway
REACT_216714
Innate Immune System pathway
REACT_207826
Interleukin-1 signaling pathway
REACT_206833
Signaling by Interleukins pathway
REACT_211704
Toll Like Receptor 4 (TLR4) Cascade pathway
REACT_225357
Fc epsilon receptor (FCERI) signaling pathway
REACT_225194
IRAK1 recruits IKK complex pathway
REACT_217527
MyD88 cascade initiated on plasma membrane pathway
REACT_213465
TCR signaling pathway
REACT_203904
p75NTR signals via NF-kB pathway
REACT_205209
TRAF6 mediated induction of TAK1 complex pathway
KEGG
hsa04010
MAPK signaling pathway pathway
hsa04120
Ubiquitin mediated proteolysis pathway
hsa05222
Small cell lung cancer pathway
hsa04620
Toll-like receptor signaling pathway pathway
hsa04722
Neurotrophin signaling pathway pathway
hsa04144
Endocytosis pathway
hsa05200
Pathways in cancer pathway
hsa04622
RIG-I-like receptor signaling pathway pathway
hsa04621
NOD-like receptor signaling pathway pathway
hsa05140
Leishmaniasis pathway
hsa05142
Chagas disease (American trypanosomiasis) pathway
hsa04380
Osteoclast differentiation pathway
hsa05145
Toxoplasmosis pathway
hsa05160
Hepatitis C pathway
INOH
INOH website
CD4 T cell receptor signaling pathway
INOH website
IL-1 signaling pathway pathway
INOH website
Toll-like receptor signaling pathway pathway
INOH website
B cell receptor signaling pathway
PID NCI
cd40_pathway
CD40/CD40L signaling
cd8tcrpathway
TCR signaling in naïve CD8+ T cells
tcr_pathway
TCR signaling in naïve CD4+ T cells
il1pathway
IL1-mediated signaling events
p75ntrpathway
p75(NTR)-mediated signaling
bcr_5pathway
BCR signaling pathway
nfkappabcanonicalpathway
Canonical NF-kappaB pathway
p38alphabetapathway
Regulation of p38-alpha and p38-beta
p38_mkk3_6pathway
p38 MAPK signaling pathway
Cross-References
SwissProt P70196
TrEMBL
UniProt Splice Variant
Entrez Gene 22034
UniGene Mm.292729 Mm.413318
RefSeq NM_009424 XM_006499156
OMIM
CCDS CCDS16464
HPRD
IMGT
MGI ID MGI:108072
MGI Symbol Traf6
EMBL AK041172 AK155434 AL929571 BC060705 CH466519 D84655
GenPept AAH60705 BAA12705 BAC30850 BAE33263 CAM20505 EDL27656 EDL27657
RNA Seq Atlas 22034

If you use InnateDB for your research, please cite the following publication:

Breuer et al., InnateDB: systems biology of innate immunity and beyond - recent updates and continuing curation. Nucl. Acids Res. (2013) 41 (D1) 

InnateDB is being developed jointly by the Brinkman Laboratory (Simon Fraser University, British Columbia, Canada), the Hancock Laboratory (University of British Columbia, Vancouver, British Columbia) and the Lynn EMBL Australia Group (South Australian Health & Medical Research Institute and Flinders University, Adelaide, Australia).

Funding is currently provided by Allergen and EMBL Australia. Previous funding has been provided by Genome Canada, the Foundation for the National Institutes of Health through the Grand Challenges in Global Health initiative and by Teagasc. InnateDB curated interactions are licensed under the Design Science License. All other data is licensed under the terms of the originating database. Contact: innatedb-mail@sfu.ca