TRAF6

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]

TRAF6 Gene(Protein Coding) TNF Receptor Associated Factor 6

E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2 (PubMed:11057907, PubMed:18347055, PubMed:19713527, PubMed:19465916).
Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation (PubMed:19675569).
Leads to the activation of NF-kappa-B and JUN (PubMed:16378096, PubMed:17135271).
Seems to also play a role in dendritic cells (DCs) maturation and/or activation (By similarity).
Represses c-Myb-mediated transactivation, in B-lymphocytes (PubMed:18093978, PubMed:18758450).
Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (PubMed:8837778, PubMed:19825828, PubMed:12140561).
Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation (By similarity).
Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production (By similarity).
Participates also in the TCR signaling by ubiquitinating LAT (PubMed:25907557, PubMed:23514740).

Biological Process activation of NF-kappaB-inducing kinase activity Source:UniProtKB1 Publication
Biological Process activation of protein kinase activity Source:UniProtKB1 Publication
Biological Process antigen processing and presentation of exogenous peptide antigen via MHC class II Source:Ensembl
Biological Process bone resorption Source:Ensembl
Biological Process cell development Source:Ensembl
Biological Process cellular response to cytokine stimulus Source:ARUK-UCL1 Publication
Biological Process cellular response to DNA damage stimulus Source:UniProtKB-KW
Biological Process cellular response to lipopolysaccharide Source:MGI1 Publication
Biological Process cytoplasmic pattern recognition receptor signaling pathway Source:Reactome
Biological Process Fc-epsilon receptor signaling pathway Source:Reactome
Biological Process I-kappaB kinase/NF-kappaB signaling Source:Reactome
Biological Process in utero embryonic development Source:Ensembl
Biological Process interleukin-1-mediated signaling pathway Source:GO_Central1 Publication
Biological Process interleukin-17-mediated signaling pathway Source:Ensembl
Biological Process MyD88-dependent toll-like receptor signaling pathway Source:Reactome
Biological Process myeloid dendritic cell differentiation Source:Ensembl
Biological Process negative regulation of DNA-templated transcription Source:UniProtKB1 Publication
Biological Process negative regulation of transcription by RNA polymerase II Source:UniProtKB1 Publication
Biological Process neural tube closure Source:Ensembl
Biological Process odontogenesis of dentin-containing tooth Source:Ensembl
Biological Process ossification Source:UniProtKB-KW
Biological Process osteoclast differentiation Source:Ensembl
Biological Process positive regulation of DNA-binding transcription factor activity Source:BHF-UCL1 Publication
Biological Process positive regulation of I-kappaB kinase/NF-kappaB signaling Source:UniProtKB1 Publication
Biological Process positive regulation of interleukin-12 production Source:Ensembl
Biological Process positive regulation of interleukin-2 production Source:UniProtKB1 Publication
Biological Process positive regulation of interleukin-6 production Source:Ensembl
Biological Process positive regulation of JNK cascade Source:GO_Central1 Publication
Biological Process positive regulation of JUN kinase activity Source:BHF-UCL1 Publication
Biological Process positive regulation of leukocyte adhesion to vascular endothelial cell Source:ARUK-UCL1 Publication
Biological Process positive regulation of lipopolysaccharide-mediated signaling pathway Source:Ensembl
Biological Process positive regulation of NF-kappaB transcription factor activity Source:UniProtKB2 Publications
Biological Process positive regulation of NIK/NF-kappaB signaling Source:ARUK-UCL1 Publication
Biological Process positive regulation of osteoclast differentiation Source:UniProtKB1 Publication
Biological Process positive regulation of protein ubiquitination Source:BHF-UCL1 Publication
Biological Process positive regulation of T cell cytokine production Source:UniProtKB1 Publication
Biological Process positive regulation of T cell proliferation Source:Ensembl
Biological Process positive regulation of transcription by RNA polymerase II Source:BHF-UCL1 Publication
Biological Process positive regulation of transcription regulatory region DNA binding Source:BHF-UCL1 Publication
Biological Process protein autoubiquitination Source:UniProtKB2 Publications
Biological Process protein K63-linked ubiquitination Source:UniProtKB2 Publications
Biological Process protein polyubiquitination Source:UniProtKB2 Publications
Biological Process regulation of apoptotic process Source:InterPro
Biological Process regulation of I-kappaB kinase/NF-kappaB signaling Source:GO_Central1 Publication
Biological Process regulation of immunoglobulin production Source:Ensembl
Biological Process response to interleukin-1 Source:UniProtKB1 Publication
Biological Process stimulatory C-type lectin receptor signaling pathway Source:Reactome
Biological Process T cell receptor signaling pathway Source:UniProtKB1 Publication
Biological Process T-helper 1 type immune response Source:Ensembl
Biological Process tumor necrosis factor-mediated signaling pathway Source:GO_Central1 Publication

Cytoplasm
Cytoplasm, cell cortex
Nucleus
Lipid droplet
Found in the nuclei of some aggressive B-cell lymphoma cell lines as well as in the nuclei of both resting and activated T- and B-lymphocytes. Found in punctate nuclear body protein complexes. Ubiquitination may occur in the cytoplasm and sumoylation in the nucleus. RSAD2/viperin recruits it to the lipid droplet (By similarity).

Sumoylated on Lys-124, Lys-142 and Lys-453 with SUMO1.
Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (PubMed:19825828).
Polyubiquitinated on Lys-124; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappaB signaling upon DNA damage (PubMed:25861989).
LRRC19 induces 'Lys-63' ubiquitination (PubMed:25026888).