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FLASH GENE
Symbol TRAF6 contributors: mct/pgu - updated : 08-01-2018
HGNC name TNF receptor-associated factor 6
HGNC id 12036
Location 11p13      Physical location : 36.510.722 - 36.531.822
Synonym name
  • tumor necrosis factor (TNF)-receptor-associated factor 6
  • interleukin-1 signal transducer
  • RING finger protein 85
  • E3 ubiquitin-protein ligase TRAF6
  • Synonym symbol(s) RNF85, MGC:3310
    EC.number 6.3.2.-
    DNA
    TYPE functioning gene
    SPECIAL FEATURE head to head
    STRUCTURE 21.10 kb     8 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Binding site
    text structure Pro-X-Glu-X-X (aromatic/acidic residues) binding motifs
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    7 splicing 2515 59.1 522 - 2006 16921377
  • variant 2
  • 8 splicing 2608 59.1 522 - 2006 16921377
  • variant 1
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   moderately
    Endocrineparathyroid   highly
    Nervousbrain   moderately
    Reproductivefemale systemplacenta  highly
    Respiratorylung   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  highly
    Muscularstriatumskeletal  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal RING zinc finger, belonging to a growing family of Ubiquitin ligases, that functions as an E3 ubiquitin (Ub) ligase facilitating its own site-specific ubiquitination through the generation of a Lys-63-linked poly-Ub chain
  • a stretch of zinc fingers coiled coil leucine zipper domain
  • ZF1 domain interacts directly with UBE2N or indirectly by stabilizing some structural elements other than the RING itself
  • a C terminal TRAF domain, required for self association (dimerization) and receptor binding, and facilitating oligomerization and sequence-specific interaction with receptors or other adaptor proteins, sufficient to mediate its association with mutant PARK7 but not PARK7 wt protein
  • a MATH domain and myosin tail
  • a proline-rich Src homology 3 domain-binding motif interacts directly with activated Src family kinase (SFK) to couple LPS engagement of TLR4 to SFK activation
  • a coiled-coil domain which interacts with IKBKG, and required for NFKB activation
  • HOMOLOGY
    Homologene
    FAMILY
  • TNF receptor-associated factor family
  • A subfamily
  • CATEGORY adaptor , signaling cytokine
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    basic FUNCTION
  • involved in the activation of NFKB by TNFRSFs, in turn activating the kinase activity of SRC
  • involved in the regional control of programmed cell death within the developing CNS and in regulation of several signaling cascades in adaptative immunity, innate immunity and bone homeostasis
  • playing a key role in the regulation of innate immune responses by mediating signals from both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies
  • involved in the maintenance of peripheral tolerance
  • playing an essential role in TNFSF11 signaling in osteoclast progenitors
  • having a ubiquitin ligase activity in TNFSF signalling and osteoclast differentiation
  • helps maintenance of cell survival by regulating glycogen synthase kinase 3B(GSK3B) activity during TNF signalling
  • regulates TNF-mediated cell survival through PI3K-Akt-GSK3B cascades
  • TRAF6 and its E3 ligase activity are required for TRAF3-stimulated IRF7 ubiquitination
  • required with MAP3K1 by TRAF6 to activate NF-kappaB and mitogen-activated protein kinases that are critical for the optimal induction of type I interferons
  • having Ub ligase activity coordinated via the RING domain and ZF1 to supply the necessary elements in signaling by cytokines dependent upon TRAF6
  • critical substrate of TRAF3IP2, which indicates the importance of protein ubiquitination in the IL17-dependent inflammatory response
  • regulates AKT1 ubiquitination and activation
  • direct E3 ligase for AKT1 and essential for AKT1 ubiquitination, membrane recruitment, and phosphorylation upon growth-factor stimulation
  • E3 ligase responsible for K63-linked IKBKG polyubiquitination which participates in several signaling pathways controlling immunity, osteoclastogenesis, skin development and brain functions
  • role for TRAF6 in mediating atypical ubiquitination of proteins relevant for sporadic and familial Parkinson disease
  • is a new SNCA modifier through unconventional ubiquitination
  • intermediate signalling molecule involved in the signal transduction by members of the interleukin-1/Toll-like receptor (IL-1R/TLR) family
  • having an E3 ubiquitin ligase activity which depends on the integrity of an amino-terminal really interesting new gene (RING) finger motif
  • role of TRAF6 in the regulation of skeletal muscle differentiation and regeneration
  • novel role for TRAF6 and atypical ubiquitination in HD pathogenesis
  • TRAF6 and atypical ubiquitination may favor alternative fates of misfolded aggregated proteins
  • critical factor in the regulation of pro-angiogenesis signaling in endothelial cells (EC)
  • potent endogenous regulator of angiogenesis in part via its ability to inhibit SRC family kinase activity
  • is a pivotal signaling element in a final common pathway for the host response to a subset of injurious stimuli, including bacterial LPS, for life-threatening vascular leak syndromes
  • TRAF6-dependent signaling may be a central pathway in osteoclast differentiation
  • plays an important role in tumorigenesis, invasion and metastasis
  • negatively regulates the JAK-STAT signaling pathway by binding to STAT3 and mediating its ubiquitination
  • key activator of NFKB, playing a critical role in the regulation of innate immune responses and their connection to adaptive immune responses
  • critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs)
  • role for TRAF6 in directing DC maintenance of intestinal immune tolerance through balanced induction of Treg versus Th2 cell immunity
  • TRAF6-mediated ubiquitination of APPL1 is a vital step for the hepatic actions of insulin through modulation of membrane trafficking and activity of AKT1
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • the serine/threonine kinase IRAK1 in response to IL1 mediated by the IL-1R pathway
  • mediating downstream of TRADD and TRAF2, the LMP1 (oncogenic latent membrane protein 1 of Epstein-Barr virus) signaling to p38 mitogen-activated protein kinase via a MAPK6 dependent pathway
  • interacting with UBE2N
  • interacting with TRAF4 and TICAM1 (silencer in TLR-mediated signaling)
  • activates the NFKB and MAPK cascades
  • MAPKBP1 interacted with not only NR2C2, but also with its upstream regulators, TNF-receptor associated factors 2 and 6 (TRAF2 and TRAF6)
  • functions together with a ubiquitin-conjugating enzyme complex consisting of UBE2N and UBE2V1 to catalyse Lys 63-linked polyubiquitination, which activates the MAP3K7 kinase complex
  • OTUB1 and -2 interacted with TRAF3 and TRAF6, two E3 ubiquitin ligases required for virus-triggered IRF3 and NF-kappaB activation, respectively
  • NUMBL directly binds to TRAF6, and down-regulates TRAF6 protein level and shortens its half-life
  • important interaction between IKBKG and TRAF6 (a new binding site for TRAF6 located at the N-terminus of IKBKG and recognized by the coiled-coil domain of TRAF6)
  • NFKB1 activation by CSF2RB is dependent on TNFR-associated factor 6 (TRAF6) and association of TRAF6 with CSF2RB requires a consensus-binding motif found in other molecules known to interact with TRAF6
  • stimulates the accumulation of insoluble and polyubiquitinated mutant PARK7 into cytoplasmic aggregates
  • binds SNCA and enhances its ubiquitination with atypical chains
  • essential for IL17A/TRAF3IP2-mediated activation of NFKB
  • interacts with and ubiquitinates WT and mutant HTT
  • RANBP9 participates in gene transcription by binding to TRAF6
  • interacting with USP4 that is a deubiquitinase targeting TRAF2 and TRAF6 for deubiquitination
  • bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6
  • negative regulator of both endogenous as well as inducible expression of VEGFA in
  • physically interacts with Src family kinase (SFKs), and during this interaction, TRAF6 catalyzes Lys63-linked ubiquitination of SFKs that in turn reciprocally tyrosine phosphorylate TRAF6 in response to LPS
  • RNF8 interacts with UBE2N in a manner that is similar to that of the RING-type E3 ubiquitin ligase TRAF6 and the U-box-type E3 ubiquitin ligase, STUB1
  • TRAF6, was critical for IL17A-induced TRAF3IP2 phosphorylation, and for IL17A-induced TBK1 activation, its association with TRAF3IP2, and consequent TRAF3IP2 phosphorylation
  • TRAF6 is a new STAT3 interactor
  • UBE2O is a novel negative regulator of TRAF6-dependent NFKB signaling
  • LAT plays an adapter role in TCR/CD28-induced activation of TRAF6
  • physical association of TLR9, ICAM1 and TRAF6 leads to activation of noncanonical NFKB1 signalling
  • NUMBL could decrease the expression of TRAF6, CCND1, and MMP9 and increase the expression of CASP3
  • PSEN1, PSEN2 are novel substrates for TRAF6-mediated K63-linked ubiquitination and ubiquitination of presenilins by TRAF6 increases presenilin holoprotein levels and reduced TRAF6 ubiquitination of presenilins results in reduction of calcium release from the endoplasmic reticulum
  • TRAF6 functions to upregulate HIF1A expression and promote tumor angiogenesis
  • OTUD7B regulates inflammatory responses to hypoxia in endothelial cells by targeting TRAF6 for deubiquitination
  • ITCH interacts with the deubiquitinating enzyme and is required for deubiquitination of TRAF6, thus limiting TNFSF11-induced osteoclast formation
  • WWP1 could degrade TRAF6, but not IRAK1, in the proteasome pathway
  • association of PINK1 with SARM1 and TRAF6 is an important step for mitophagy
  • SIK1 and SIK3 negatively regulate TLR4-mediated signaling through the interruption of TAB2-TRAF6 complex and thereby the inhibition of ubiquitination of TRAF6
  • inhibits non-canonical TGFB1 signalling by recruiting the deubiquitinase TNFAIP3 to TRAF6
  • TRAF6 mediates ubiquitination of the midbody ring localized protein KIF23/MKLP1
  • TRAF5 negatively regulated the association of TAB2 with its signaling partner TRAF6 after TLR ligation in B cells
  • PPP1CC physically interacts with the E3 ubiquitin ligase TRAF6, and enhances the activity of TRAF6 towards itself and substrates such as IKBKG
  • plays a critical role in the regulation of macrophage homeostasis by inhibiting TRAF6-mediated AKT1 activation
  • role for TICAM2 in TLR4-mediated signaling in regulating inflammatory responses via its interaction with TRAF6, distinct from its role as a bridging adaptor between TLR4 and TICAM1
  • ECSIT interacts with TRAF6, is ubiquitinated, and contributes to bactericidal activity during Toll-like receptor (TLR) signaling
  • TRAF6 is required for CSF2-induced ubiquitination and activation of AKT1
  • TANK negatively regulates NFKB1 activation by DNA damage via inhibiting ubiquitination of TRAF6
  • SQSTM1 is a critical regulator in CD40-mediated NFKB1 signaling via TRAF6
  • BSG/CD147, a critical molecule for cancer cell invasion and metastasis, is a novel interacting partner of TRAF6
  • VAV3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between TRAF6-binding sites (T6BSs) and the IVVY motif in the TNFRSF11A signaling complex
  • TRAF6-mediated degradation of DOK3 is required for production of IL6 and TNF in TLR9 signaling
  • YOD1 is a novel interactor of TRAF6 (antagonizes TRAF6/p62-dependent IL1 signaling to NFKB1)
  • TRAF6 is also required for the TNFSF13B-mediated activation of NFKB1 signal pathway
  • silencing METTL3 could sustain long-chain fatty acids (LCFAs) absorption through blocking the TRAF6-dependent inflammation response
  • cell & other
  • mediating the activation of NF-kappa B and JNK pathways by XEDAR (X linked ectodermal dysplasia receptor)
  • REGULATION
    induced by IFNG induced degradation of TRAF6 by the ubiquitin-proteasome system
    inhibited by TIZ
    Other deglutathionylation of TRAF6 by GLRX is needed for the efficient auto-polyubiquitination and the subsequent activation of the molecule
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in post-mortem brains from Huntington disease patients where it is found in the insoluble fraction
    constitutional       loss of function
    specific inhibition of TRAF6 improves satellite cell activation and skeletal muscle regeneration through upregulation of Notch signaling and reducing the inflammatory repertoire
    tumoral     --over  
    in osteosarcoma tissues compared to normal bone tissue
    tumoral     --over  
    in primary as well as metastatic melanoma tumors and melanoma cell lines
    Susceptibility to osteoporosis
    Variant & Polymorphism other variant increasing the risk of osteoporosis
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Traf6(-/-) mice display exencephaly and failure of neural tube closure
  • TRAF6-deficient T cells exhibit hyperactivation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and become resistant to suppression by CD4+ CD25+ regulatory T-cells