InnateDB: Systems Biology of the Innate Immune Response

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

IDBP-40104

TNF receptor-associated factor 6

IDBP-586776

TNF receptor-associated factor 6

Protein Structure

Useful resources

Stemformatics EHFPI ImmGen

InnateDB Annotation

Summary

PMID 16184196

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

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

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

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

TRAF6 negatively regulates TNFalpha-induced NF-kappaB activation through its ubiquitin ligase activity.

PMID 12140561

TRAF6 regulates several signalling cascades in innate immunity, adaptive immunity and bone homeostasis.

PMID 20449947

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

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

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

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. (Demonstrated in mice)

PMID 24670424

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

MIR146A is a potent negative regulator of the innate immune response in keratinocytes through downregulation of the IRAK1/TRAF6/NFκB pathway.

PMID 25027037

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

ECSIT binds to MAP3K7 and TRAF6 to form a complex that plays a pivotal role in activating TLR4-mediated NF-kB signalling.

PMID 26221041

Reversible arginine methylation of TRAF6 is regulated by PRMT1 and JMJD6 and this in turn regulates TRAF6-dependent TLR signalling.

PMID 26385923

MAVS directly interacts with TRAF6 through its potential TRAF6-binding motif 2.

InnateDB Annotation from Orthologs

Summary

PMID 21185369

[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.

PMID 21220427

[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.

PMID 22033459

[Mus musculus] Traf6 is degraded in the proteasome upon TLR stimulation in macrophages.

PMID 23951545

[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.

PMID 26048146

[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

PMID 25808990

[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.

PMID 26503954

[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.

PMID 26305951

[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

ENSMUSG00000027164

View Gene Order

ENSBTAG00000036009

Not yet available

Pathways

NETPATH

NetPath_7

TGF_beta_Receptor pathway

TNFalpha pathway

TCR pathway

IL1 pathway

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

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 na�ve CD8+ T cells

tcr_pathway

TCR signaling in na�ve 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

Q9Y4K3

TrEMBL

UniProt Splice Variant

Entrez Gene

7189

UniGene

Hs.444172

RefSeq

NM_004620 NM_145803

HUGO

HGNC:12036

OMIM

602355

CCDS

CCDS7901

HPRD

03833

IMGT

EMBL

AC009656 AC061999 AK292978 AY228337 BC031052 CH471064 U78798

GenPept

AAB38751 AAH31052 AAO38054 BAF85667 EAW68119 EAW68120 EAW68122

RNA Seq Atlas

7189