Affinage

TRAF6

TNF receptor-associated factor 6 · UniProt Q9Y4K3

Length
522 aa
Mass
59.6 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAF6 is a RING-domain E3 ubiquitin ligase that functions as a central signaling hub downstream of IL-1R/TLR, TNFR superfamily, TGF-β, and antigen receptors, coupling receptor activation to NF-κB, JNK, and p38 MAPK pathways. Upon stimulation, TRAF6 oligomerizes and, together with the Ubc13/Uev1A E2 complex, catalyzes K63-linked polyubiquitin chain synthesis on itself and a broad array of substrates—including TβRI, FOXP3, EZH2, BECN1, ULK1, hDNA2, cGAS, PINK1, and PIK3CA—thereby serving as a non-proteolytic scaffold that recruits and activates TAK1-TAB and IKK kinase complexes (PMID:15492226, PMID:18922473, PMID:30886050, PMID:27869166). TRAF6 E3 ligase activity is essential for some pathways (IL-33/ST2L signaling, FOXP3 ubiquitination in Tregs) but is partially redundant with Pellino E3 ligases in IL-1-induced NF-κB activation, revealing separable scaffold and catalytic functions (PMID:18603409, PMID:28404732). TRAF6 activity is regulated by S-glutathionylation of its RING domain, RSK2-mediated phosphorylation at S46/47/48, inhibitory interactions (PRDX1, syntenin, Sufu, OTUB1), K48-linked ubiquitination-dependent degradation (counteracted by IPMK), and liquid–liquid phase separation that promotes its oligomerization and autoubiquitination during inflammatory signaling (PMID:21078302, PMID:29563609, PMID:37441604, PMID:28439546).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Establishing TRAF6 as a non-redundant adaptor for multiple innate immune and TNFR superfamily pathways: TRAF6 knockout mice revealed essential roles in RANK-dependent osteoclastogenesis, IL-1, CD40, and LPS signaling, defining the breadth of TRAF6's signaling scope.

    Evidence TRAF6 knockout mice with in vitro signaling assays showing osteopetrosis and impaired cytokine responses

    PMID:10215628

    Open questions at the time
    • Enzymatic mechanism of TRAF6 was unknown
    • Whether TRAF6 functions as scaffold versus enzyme was not resolved
    • Downstream kinase targets not yet mapped
  2. 2000 Medium

    Identifying distinct TRAF6 signaling complexes: T6BP was found to associate specifically with TRAF6 in an IL-1/IRAK-dependent manner, revealing that TRAF6 participates in stimulus-specific multiprotein complexes rather than a single uniform signaling module.

    Evidence Co-immunoprecipitation with domain mapping showing T6BP binds TRAF6 RING/zinc-finger domains, with IL-1-dependent complex formation

    PMID:10920205

    Open questions at the time
    • T6BP function in TRAF6 signaling not defined
    • No structural data on the T6BP-TRAF6 interface
    • Stoichiometry of endogenous complexes unknown
  3. 2004 High

    Reconstituting the TRAF6 ubiquitination cascade in vitro resolved the catalytic mechanism: TIFA-induced TRAF6 oligomerization drives K63-linked polyubiquitination via the Ubc13/Uev1A E2, which activates TAK1 and IKK; the coiled-coil domain bridges TRAF6 to its E2 rather than serving as a ubiquitin acceptor.

    Evidence Cell-free reconstitution with purified TRAF6, TAK1 complex, and Ubc13-Uev1A; domain deletion/mutation analysis with NF-κB reporters

    PMID:15465037 PMID:15492226

    Open questions at the time
    • Crystal structure of TRAF6 RING–E2 complex not yet available
    • Physiological ubiquitin acceptor sites on TRAF6 not mapped
    • Redundancy with other E3 ligases not tested
  4. 2007 Medium

    Structural characterization of the TRAF-C domain explained how TRAF6 uniquely engages both TNFR superfamily and IL-1R/TLR superfamily receptors, resolving its dual receptor specificity.

    Evidence Structural and biochemical studies of receptor-binding motifs in the TRAF-C domain

    PMID:17633022

    Open questions at the time
    • Full-length TRAF6 structure not determined
    • Binding affinities for diverse receptors not systematically compared
  5. 2008 High

    TRAF6's substrate repertoire expanded beyond innate immune receptors: TRAF6 was shown to mediate TGF-β-induced Smad-independent JNK/p38 activation via K63-ubiquitination and TAK1 recruitment, to be essential for IL-33/ST2L signaling (requiring E3 ligase activity), to function in RIG-I/MDA5 antiviral IFN-α/β induction via MEKK1, and to regulate GSK3β activity controlling TNF-induced cell death.

    Evidence TRAF6-deficient MEFs with signaling readouts, C70A ligase-dead mutant rescue, epistasis with TAK1-KO, ROS and JNK assays

    PMID:18202703 PMID:18603409 PMID:18922473 PMID:18984593

    Open questions at the time
    • Whether TRAF6 directly ubiquitinates TGF-β receptor components was unclear
    • The relative contribution of TRAF6 E3 activity versus scaffold function was unresolved across pathways
  6. 2009 Medium

    TRAF6-mediated K63-linked ubiquitination of MLK3 was identified as a mechanism for IL-1β-induced MLK3 kinase activation, broadening the kinase substrates of TRAF6.

    Evidence Co-immunoprecipitation, RNAi of TRAF6, in vitro kinase assays, K63-ubiquitination assays

    PMID:19586614

    Open questions at the time
    • In vitro reconstitution of TRAF6-mediated MLK3 ubiquitination not performed
    • Specific ubiquitinated lysines on MLK3 not mapped
  7. 2010 High

    Multiple layers of TRAF6 regulation were uncovered: GRX-1-mediated deglutathionylation of the RING domain licenses TRAF6 autoubiquitination upon IL-1 stimulation, while NUMBL promotes K48-linked ubiquitination and degradation of TRAF6 to limit NF-κB; concurrently, muscle-specific TRAF6 deletion revealed TRAF6 as a master regulator of skeletal muscle atrophy via NF-κB, MAPK, AMPK, and autophagy.

    Evidence S-glutathionylation assays with GRX-1 RNAi; NUMBL Co-IP with K48/K63 linkage-specific Ub assays; muscle-specific TRAF6 KO mice in denervation and cancer cachexia models

    PMID:20079715 PMID:21078302 PMID:21187332

    Open questions at the time
    • Glutathionylation site on TRAF6 RING domain not mapped at residue level
    • NUMBL-TRAF6 E3 ligase responsible for K48-Ub not identified
    • How TRAF6 activates AMPK in muscle was not established
  8. 2011 High

    TRAF6 was shown to directly ubiquitinate TβRI with K63-linked chains in a PKCζ-dependent manner, triggering TACE-mediated cleavage and nuclear translocation of the TβRI intracellular domain to activate invasion genes, revealing a non-canonical TGF-β signaling axis.

    Evidence Co-immunoprecipitation, K63-Ub assays, TACE cleavage assays, invasion assays, tumor tissue IHC

    PMID:21629263

    Open questions at the time
    • Specific lysine residues on TβRI targeted by TRAF6 not identified
    • Whether this pathway operates in non-cancer contexts was unclear
  9. 2013 Medium

    TRAF6's K63-linked ubiquitination activity was extended to non-signaling contexts: TRAF6 ubiquitinates HIF-1α to stabilize it independently of oxygen and promotes tumor angiogenesis, and ubiquitinates PINK1 (with SARM1) on depolarized mitochondria to facilitate parkin recruitment and mitophagy.

    Evidence Co-immunoprecipitation, K63-Ub assays, protein stability assays, angiogenesis assays; SARM1-TRAF6-PINK1 complex analysis with site-specific K433 mutagenesis

    PMID:23722539 PMID:23885119

    Open questions at the time
    • In vitro reconstitution of TRAF6-mediated HIF-1α ubiquitination not shown
    • Whether SARM1 is required for all TRAF6-PINK1 interactions was untested
    • Pathogenic PINK1 mutations reducing TRAF6 binding tested only in overexpression
  10. 2014 Medium

    TRAF6 emerged as a key node in growth factor signaling: CKIP-1 terminates TRAF6-dependent K63-ubiquitination and membrane recruitment of Akt to limit macrophage proliferation, while EGFR-phosphorylated DCBLD2 recruits and activates TRAF6 to drive AKT-dependent tumorigenesis.

    Evidence CKIP-1 KO mice with Akt ubiquitination assays; DCBLD2 Y750 mutagenesis with Co-IP and tumor studies

    PMID:24777252 PMID:25061874

    Open questions at the time
    • Direct substrate relationship between TRAF6 and Akt ubiquitination not reconstituted in vitro
    • DCBLD2-TRAF6 structural basis not determined
  11. 2016 High

    The substrate landscape of TRAF6 broadened to include chromatin regulators, membrane trafficking targets, and mRNA decay machinery: TRAF6 ubiquitinates EZH2 with K63 chains leading to its degradation, ubiquitinates Basigin/CD147 promoting its plasma membrane localization and MMP9-driven invasion, and ubiquitinates DCP1a-associated factors to drive P-body assembly and constitutive inflammatory mRNA decay.

    Evidence In vitro ubiquitination with recombinant EZH2 and TRAF6-C70A control; BSG K63-Ub assays with invasion readouts; DCP1a Co-IP and mRNA decay assays

    PMID:26769849 PMID:27315556 PMID:27869166

    Open questions at the time
    • Whether TRAF6 directly ubiquitinates DCP1a or acts indirectly was ambiguous
    • Mechanism connecting K63-Ub of EZH2 to its degradation (normally K48-mediated) unclear
  12. 2017 High

    A critical revision of the TRAF6 model showed that Pellino E3 ligases compensate for TRAF6 E3 activity in IL-1 signaling (triple-KO required to abolish K63-Ub), while RANKL-induced osteoclastogenesis proceeds with E3 ligase-inactive TRAF6, formally separating TRAF6's scaffold and catalytic functions; additionally, IPMK and syntenin were identified as regulators that stabilize and sequester TRAF6, respectively, and RSK2 phosphorylation at S46/47/48 licenses TRAF6 activation.

    Evidence Pellino1/2 double-KO plus TRAF6-KO triple cell lines; TRAF6[L74H] knockin mice; IPMK myeloid-KO with K48-Ub assays; syntenin Co-IP/competition; in vitro RSK2 kinase assay

    PMID:18234474 PMID:28404732 PMID:28439546 PMID:29563609

    Open questions at the time
    • Structural basis for TRAF6 scaffold function independent of E3 activity not resolved
    • Whether Pellino compensation occurs in all TLR pathways untested
    • RSK2 phosphorylation sites validated in vitro but not confirmed with phospho-specific antibodies in vivo
  13. 2018 High

    Structural and biophysical studies revealed how TRAF6 functions in higher-order signaling assemblies: cryo-EM showed TRAF6 cooperatively decorates BCL10-MALT1 filaments enabling threshold NF-κB activation downstream of antigen receptors; structural modeling revealed a concerted allosteric mechanism in the TRAF6 RING dimer for ubiquitin transfer; and multiple negative regulators (PRDX1, YAP) were shown to restrain TRAF6 activity.

    Evidence Cryo-EM of BCL10 CARD filament–TRAF6 assemblies; structural modeling of RING dimer–Ub–E2 complex; PRDX1 Co-IP with ECSIT/BECN1 ubiquitination assays; endothelial YAP KO mice with TRAF6 rescue

    PMID:29382759 PMID:29432170 PMID:29794022 PMID:29929436

    Open questions at the time
    • Atomic-resolution structure of full-length TRAF6 in a signalosome not available
    • How TRAF6 transitions from resting to active state on filaments not resolved
  14. 2019 High

    TRAF6-mediated K63 ubiquitination was shown to regulate nuclear trafficking and function of key transcription factors and DNA repair enzymes: TRAF6 ubiquitinates FOXP3 at K262 to maintain its nuclear localization and Treg function, ubiquitinates hDNA2 to promote its nuclear import and homology-directed repair, and ubiquitinates ULK1 to drive autophagy; BANK1 was identified as a TRAF6 adapter in B cell TLR signaling.

    Evidence Treg-specific TRAF6 conditional KO with FOXP3-K262R mutagenesis; hDNA2 nuclear fractionation and DNA repair assays; ULK1 stability and autophagy readouts; BANK1 binding motif mutations and K63-Ub assays

    PMID:30886050 PMID:30929559 PMID:31216032 PMID:31243359

    Open questions at the time
    • Whether TRAF6-mediated FOXP3 ubiquitination is direct (in vitro reconstitution) was not shown
    • Physiological signals activating GCA-TRAF6-ULK1 axis beyond CML not characterized
  15. 2021 Medium

    OTUB1 was identified as a deubiquitinase that directly binds TRAF6 and suppresses its K63-linked polyubiquitination, attenuating downstream ASK1 signaling in hepatocytes and protecting against NASH.

    Evidence IP-mass spectrometry, Co-immunoprecipitation, K63-Ub assays, hepatocyte-specific OTUB1 overexpression mouse model

    PMID:34591986

    Open questions at the time
    • Whether OTUB1 acts on TRAF6 directly or via K63-chain editing not distinguished
    • Catalytic versus non-catalytic mechanism of OTUB1 on TRAF6 not resolved
  16. 2022 Medium

    USP15 was shown to oppose the TRAF6-BECN1 autophagy axis by deubiquitinating BECN1, revealing how TRAF6-dependent K63 ubiquitination of BECN1 is reversibly regulated to tune autophagy and cell invasion.

    Evidence CRISPR KO of USP15, Co-IP, deubiquitination assays, autophagy and invasion readouts

    PMID:35422093

    Open questions at the time
    • Direct in vitro reconstitution of USP15-mediated BECN1 deubiquitination not performed
    • Whether USP15 competes with TRAF6 for BECN1 binding not tested
  17. 2023 High

    A biophysical mechanism for TRAF6 activation was established: TRAF6 undergoes liquid–liquid phase separation during LPS-induced inflammation, which is essential for its oligomerization, autoubiquitination, and NF-κB activation; the inhibitor Sufu blocks TRAF6 phase separation and oligomerization.

    Evidence In vitro phase separation with purified TRAF6, FRAP, Native-PAGE, myeloid-specific Sufu KO mice with TRAF6 depletion rescue

    PMID:37441604

    Open questions at the time
    • Molecular determinants (IDRs, post-translational modifications) driving TRAF6 phase separation not mapped
    • Whether phase separation occurs for all TRAF6 signaling contexts or only TLR4 not tested
  18. 2024 Medium

    TRAF6 was linked to immune evasion via K63-linked ubiquitination of YAP1 promoting PD-L1 transcription in melanoma, and to viral exploitation by HIV-1 Tat which directly enhances TRAF6 oligomerization and ubiquitination to activate NF-κB-driven viral transcription.

    Evidence CRISPR interference screen with Co-IP and K63-Ub assays for YAP1-PD-L1 axis; Tat-TRAF6 Co-IP with oligomerization and ubiquitination assays

    PMID:38241362 PMID:38583649

    Open questions at the time
    • Whether Tat-TRAF6 interaction is direct or bridged not confirmed with purified proteins
    • TRAF6-YAP1 ubiquitination sites not mapped
    • Therapeutic potential of TRAF6 inhibition for PD-L1 regulation not validated in clinical models

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full-length atomic structure of TRAF6 in active signalosome complexes, the molecular determinants governing TRAF6 liquid–liquid phase separation across diverse signaling contexts, systematic identification of all direct TRAF6 substrates versus indirect targets, and the in vivo significance of separable scaffold versus E3 ligase functions across the full range of TRAF6-dependent pathways.
  • No full-length TRAF6 structure in a signalosome complex
  • Phase separation determinants unmapped
  • Systematic substrate identification lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0016874 ligase activity 5 GO:0060090 molecular adaptor activity 4
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 6 R-HSA-392499 Metabolism of proteins 4 R-HSA-9612973 Autophagy 3 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
BECN1EZH2FOXP3IRAK1TAK1TGFBR1UBE2NUBE2V1
Complex memberships
CBM (CARMA1-BCL10-MALT1) signalosomesIRAK1-MyD88-TRAF6 myddosomeTRAF6-Ubc13/Uev1A E2-E3 complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TRAF6 is essential for osteoclast function and bone remodeling downstream of RANK/OPGL signaling, and is required for IL-1, CD40, and LPS signaling, as demonstrated by TRAF6 knockout mice showing osteopetrosis and defective signaling responses. Knockout mouse model with in vitro signaling assays Genes & development High 10215628
2004 TIFA activates IKK by promoting oligomerization and Lys63-linked polyubiquitination of TRAF6; only oligomeric forms of TIFA can activate IKK, demonstrated in an in vitro reconstitution system with purified TRAF6, TAK1 complex, and Ubc13-Uev1A. In vitro reconstitution with purified proteins, cell-free extract IKK activation assay Proceedings of the National Academy of Sciences of the United States of America High 15492226
2004 The coiled-coil domain of TRAF6 is essential for its auto-ubiquitination and NF-κB activation; it serves as a bridge to recruit Ubc13/Uev1A rather than as the target site of polyubiquitin chain attachment. Domain deletion/mutation analysis, NF-κB reporter assays, ubiquitination assays Biochemical and biophysical research communications Medium 15465037
2007 Structural and biochemical studies defined the molecular basis for TRAF6's unique binding specificity, revealing how its TRAF-C domain mediates interactions with both TNFR superfamily and IL-1R/TLR superfamily receptors. Structural and biochemical studies, receptor binding motif analysis Advances in experimental medicine and biology Medium 17633022
2008 TRAF6 is specifically required for TGF-β-induced, Smad-independent activation of JNK and p38; the TRAF homology domain of TRAF6 physically interacts with TGF-β receptors, and TGF-β induces K63-linked ubiquitination of TRAF6 and promotes TRAF6-TAK1 association. Co-immunoprecipitation, ubiquitination assays, TRAF6-deficient MEFs with signaling readouts Molecular cell High 18922473
2008 TRAF6 is critical for IFN-α/β induction in response to viral infection and intracellular dsRNA via the RIG-I/MDA5-IPS-1 pathway, activating NF-κB, JNK, and p38 but not IRF3; MEKK1 (not TAK1) acts downstream of TRAF6 for IFN-β induction in this pathway. TRAF6-deficient and TAK1-deficient MEFs, siRNA knockdown, reporter assays, forced expression The Journal of biological chemistry High 18984593
2008 TRAF6 plays a pivotal role in IL-33/ST2L signaling; TRAF6 deficiency abolishes IRAK recruitment to ST2L and completely inhibits IL-33-induced p38, JNK, and NF-κB activation; a TRAF6 ubiquitin ligase-dead mutant (C70A) fails to restore these responses, demonstrating that E3 ligase activity is required. TRAF6-deficient MEFs, rescue with wild-type vs. C70A mutant TRAF6, signaling assays Cellular signalling High 18603409
2008 TRAF6 deficiency leads to constitutive inactivation of GSK3β and promotes TNF-induced ROS accumulation and prolonged JNK activation leading to cell death; restoration of GSK3β activity rescues cell death in TRAF6-null cells. TRAF6-deficient 3T3 cells, reconstitution with constitutively active GSK3β, ROS and JNK assays Cell death and differentiation Medium 18202703
2010 TRAF6 mediates activation of JNK1/2, p38 MAPK, AMPK, and NF-κB in skeletal muscle during atrophy, and regulates expression of muscle-specific E3 ubiquitin ligases and autophagy-related molecules; muscle-restricted TRAF6 depletion rescues myofibril degradation, muscle fiber size, and prevents cancer cachexia. Muscle-specific TRAF6 knockout mice, denervation and cancer cachexia models, signaling assays The Journal of cell biology High 21187332
2010 Glutaredoxin-1 (GRX-1) catalyzes deglutathionylation of the RING finger motif of TRAF6; TRAF6 is S-glutathionylated under basal conditions, and deglutathionylation upon IL-1 stimulation is essential for TRAF6 auto-polyubiquitination and subsequent NF-κB activation. RNAi knockdown, S-glutathionylation assays, ubiquitination assays, NF-κB reporter Biochemical and biophysical research communications Medium 21078302
2010 NUMBL directly binds TRAF6 and promotes K48-linked polyubiquitination of TRAF6, leading to proteasomal degradation of TRAF6 and inhibition of NF-κB signaling; knockdown of NUMBL increases endogenous TRAF6 protein levels in cortical neurons. Co-immunoprecipitation, in vivo ubiquitination assays (K48 vs K63 linkage), NUMBL knockdown, half-life assays Biochemical and biophysical research communications Medium 20079715
2011 TRAF6 associates with TβRI and mediates Lys63-linked polyubiquitination of TβRI in a PKCζ-dependent manner, promoting cleavage of TβRI by TACE; the liberated TβRI intracellular domain then associates with p300 to activate invasion-related genes (Snail, MMP2). Co-immunoprecipitation, ubiquitination assays, TACE cleavage assays, invasion assays, tumor tissue IHC Nature communications High 21629263
2013 TRAF6 binds HIF-1α and mediates its K63-linked polyubiquitination, increasing HIF-1α protein levels (independent of oxygen and mRNA levels), thereby promoting tumor angiogenesis; E3 ligase activity of TRAF6 is required for this effect. Co-immunoprecipitation, K63-linked ubiquitination assays, protein stability assays, angiogenesis assays Cancer research Medium 23722539
2013 SARM1 and TRAF6 form a complex with PINK1 on depolarized mitochondria; SARM1 promotes TRAF6-mediated K63-linked ubiquitination of PINK1 at lysine 433, which is important for PINK1 stabilization, parkin recruitment, and mitophagy; some pathogenic PINK1 mutations reduce complex formation and ubiquitination. Co-immunoprecipitation, K63-linked ubiquitination assays, PINK1/parkin recruitment assays, knockdown experiments Molecular biology of the cell Medium 23885119
2014 CKIP-1 interacts with TRAF6 and terminates TRAF6-mediated K63-linked ubiquitination and plasma membrane recruitment of Akt, thereby inhibiting macrophage proliferation at late stages after M-CSF stimulation; CKIP-1 deficiency leads to macrophage-dominated splenomegaly and myeloproliferation. Co-immunoprecipitation, Akt ubiquitination assays, CKIP-1 knockout mice Cell research Medium 24777252
2014 EGFR phosphorylates DCBLD2 at Y750, which recruits TRAF6 via a TRAF6-binding motif; phospho-DCBLD2-bound TRAF6 exhibits increased E3 ubiquitin ligase activity and subsequently activates AKT to drive EGFR-dependent tumorigenesis. Co-immunoprecipitation, ubiquitination assays, mutational analysis of Y750, tumor cell lines and patient samples The Journal of clinical investigation Medium 25061874
2015 TRAF6-mediated signaling through ERK1/2, JNK1/2, and c-JUN is critical for satellite cell homeostasis and regenerative myogenesis; TRAF6/c-JUN signaling activates Pax7 transcription and represses miR-1 and miR-206 to maintain PAX7 levels; satellite cell-specific Traf6 deletion exaggerates dystrophic phenotype in mdx mice. Satellite cell-specific TRAF6 conditional knockout mice, muscle injury models, signaling assays, ChIP, miRNA analysis The Journal of clinical investigation High 26619121
2016 TRAF6 ubiquitinates Basigin (BSG/CD147) with K63-linked chains, promoting BSG recruitment to the plasma membrane and BSG-dependent MMP9 induction; TRAF6 knockdown reduces plasma membrane BSG and impairs melanoma invasion and metastasis. Co-immunoprecipitation, K63-linked ubiquitination assays, shRNA knockdown, invasion assays in vitro and in vivo Oncotarget Medium 26769849
2016 SKP2 loss upregulates TRAF6-mediated K63-linked ubiquitination of EZH2, leading to EZH2 degradation; the catalytically dead TRAF6-C70A mutant abolishes polyubiquitination of recombinant EZH2 in vitro, establishing TRAF6 as the E3 ligase for EZH2. In vitro ubiquitination assay with recombinant proteins, Co-IP, K63-Ub linkage assays, KO/KD cell lines, mouse models Oncogene High 27869166
2016 K63-linked ubiquitylation mediated by TRAF6 is required for assembly of decapping factors, P-body formation, and constitutive decay of unstable inflammatory mRNAs; TRAF6 binds DCP1a and indirectly regulates its phosphorylation and mRNA decapping activity. Co-immunoprecipitation, ubiquitination assays, DCP1a lysine mutants, P-body imaging, mRNA decay assays Molecular cell Medium 27315556
2017 TRAF6 E3 ligase activity contributes to but is not essential for IL-1-dependent K63-Ub chain formation, TAK1 activation, and IL-8 production; Pellino1 and Pellino2 compensate for TRAF6 E3 activity in this pathway. TRAF6/Pellino1/2 triple-KO abolishes all K63-Ub formation and IRAK1/IRAK4/MyD88 ubiquitination. RANKL-induced osteoclastogenesis proceeds normally with E3 ligase-inactive TRAF6, identifying scaffold functions of TRAF6 independent of its E3 activity. TRAF6 KO, Pellino1/2 double-KO, triple-KO cell lines; E3 ligase-inactive TRAF6[L74H] knockin mice; in vitro TAK1 activation with purified K63-Ub chains Proceedings of the National Academy of Sciences of the United States of America High 28404732
2017 IPMK directly binds TRAF6 (independent of IPMK catalytic activity) and stabilizes TRAF6 by blocking its K48-linked ubiquitination and proteasomal degradation, thereby sustaining TLR-induced proinflammatory signaling. Myeloid-specific IPMK KO mice, Co-immunoprecipitation, K48-Ub linkage assays, protein stability assays Science advances Medium 28439546
2017 RSK2 phosphorylates TRAF6 at serines 46, 47, and 48 in vitro; RSK2-mediated phosphorylation is required for TRAF6 K63-linked ubiquitination and downstream inflammatory signaling in the colon. In vitro kinase assay, phosphorylation site mutagenesis, RSK2 KO mice, colon inflammation model, Co-IP Oncogene Medium 29563609
2018 Cryo-EM structure of BCL10 CARD filament at 4.0-Å resolution reveals that TRAF6 cooperatively decorates CBM (CARMA1-BCL10-MALT1) filaments to form higher-order assemblies, likely enabling all-or-none NF-κB activation downstream of TCR/BCR signaling. Cryo-EM structure determination, time-lapse confocal imaging, EM of MALT1-BCL10 and TRAF6-CBM assemblies Proceedings of the National Academy of Sciences of the United States of America High 29382759
2018 The TRAF6 RING dimer employs a concerted allosteric mechanism using both subunits to promote ubiquitin transfer; the C-terminal extension of the TRAF6 RING domain mediates trans-interactions with donor ubiquitin, and N-terminal extensions engage donor-Ub in cis. Structural modeling, biochemical analysis, comparison with E3-Ub-E2 complex structures Proceedings of the National Academy of Sciences of the United States of America Medium 29432170
2018 PRDX1 interacts with the RING finger domain of TRAF6 and inhibits its ubiquitin ligase activity, suppressing ubiquitination of ECSIT (required for NF-κB activation) and BECN1 (required for autophagy); PRDX1 knockdown enhances both NF-κB activation and autophagy in response to TLR4 stimulation. Co-immunoprecipitation, RING domain interaction mapping, ubiquitination assays (ECSIT and BECN1), PRDX1 KD cell lines Autophagy Medium 29929436
2018 YAP interacts with TRAF6 to promote its ubiquitination and degradation, thereby inhibiting TRAF6-mediated NF-κB activation in endothelial cells; endothelial YAP deletion augments inflammatory responses, which are rescued by TRAF6 depletion. Co-immunoprecipitation, endothelial-specific YAP KO mice, TRAF6 depletion rescue experiments, NF-κB assays Circulation research Medium 29794022
2018 TRAF6 interacts with and ubiquitinates PIK3CA (p110α) with nonproteolytic polyubiquitin chains under serum stimulation, enhancing PI3K activation and downstream AKT phosphorylation and cell growth. Co-immunoprecipitation, ubiquitination assays, overexpression and KD of TRAF6, AKT activation readouts FEBS letters Medium 29729098
2019 TRAF6 mediates K63-linked ubiquitination of FOXP3 at lysine 262; in the absence of TRAF6 activity or upon K262R mutation, FOXP3 shows aberrant perinuclear accumulation and disrupted regulatory T cell function; TRAF6-deficient Tregs are dysfunctional in vivo. Treg-specific TRAF6 conditional KO mice, K63-ubiquitination assays, site-directed mutagenesis of FOXP3-K262, subcellular localization imaging The EMBO journal High 30886050
2019 TRAF6 binds to and mediates K63-linked polyubiquitination of hDNA2, increasing hDNA2 stability and promoting its nuclear localization; inhibiting TRAF6-mediated polyubiquitination abolishes nuclear localization of hDNA2, impairing DNA end resection and homology-directed recombination repair. Co-immunoprecipitation, K63-Ub assays, nuclear fractionation, DNA repair assays Nucleic acids research Medium 31216032
2019 GCA (grancalcin) activates TRAF6 ubiquitin ligase activity to induce K63-linked ubiquitination of ULK1, resulting in ULK1 stabilization and activation, thereby driving autophagy and imatinib resistance in CML. Co-immunoprecipitation, K63-ubiquitination assays, ULK1 stability assays, autophagy readouts Autophagy Medium 30929559
2019 TRAF6 ubiquitinates cGAS with K63-linked chains, promoting cGAS activation and downstream IFNβ production; TRAF6 knockdown reduces cGAS-induced IFNβ upon HSV-1 infection. Overexpression/knockdown of TRAF6, ubiquitination assays, IFNβ production assays, HSV-1 infection Biochemical and biophysical research communications Low 31078259
2021 OTUB1 directly binds TRAF6 and suppresses its K63-linked polyubiquitination, thereby inhibiting downstream ASK1 activation; hepatocyte-specific OTUB1 overexpression markedly alleviates NASH in mice. IP-mass spectrometry, Co-immunoprecipitation, K63-Ub assays, hepatocyte-specific overexpression mouse model Hepatology Medium 34591986
2022 USP15 interacts with BECN1 (not TRAF6) and deubiquitinates BECN1, thereby attenuating TRAF6-BECN1 axis-driven autophagy induction and lung cancer migration/invasion; USP15 KO enhances autophagy in response to TLR4 stimulation. CRISPR-Cas9 USP15 KO, Co-immunoprecipitation, deubiquitination assays, autophagy and invasion assays Cell death & disease Medium 35422093
2023 Sufu directly interacts with TRAF6, preventing TRAF6 oligomerization and autoubiquitination; TRAF6 undergoes liquid-liquid phase separation during LPS-induced inflammation, which is essential for its ubiquitination activation and NF-κB activity; Sufu inhibits TRAF6 phase separation, reducing NF-κB activation. Co-immunoprecipitation, FRAP, Native-PAGE, in vitro phase separation assays with purified proteins, myeloid-specific Sufu KO mice, TRAF6 depletion rescue Theranostics High 37441604
2024 HIV-1 Tat directly interacts with TRAF6, increasing TRAF6 oligomerization and auto-ubiquitination as well as K63-linked polyubiquitin chain synthesis, thereby enhancing NF-κB pathway activation and HIV-1 transcription. Co-immunoprecipitation, ubiquitination assays, oligomerization assays, reporter assays, TRAF6 knockdown Science advances Medium 38241362
2008 HSV UL37 tegument protein activates NF-κB signaling through direct interaction with TRAF6 via a TRAF6-binding domain in UL37; mutation of this binding site reduces NF-κB activation during early viral infection. Transfection, Co-immunoprecipitation, NF-κB reporter assay, mutant virus with altered TRAF6-binding site Proceedings of the National Academy of Sciences of the United States of America Medium 18682563
2000 T6BP (TRAF6-binding protein) specifically associates with TRAF6 through the coiled-coil region of T6BP and the N-terminal RING finger and zinc finger domains of TRAF6; IL-1 (but not TNF) induces TRAF6-T6BP complex formation in an IRAK-dependent manner; T6BP and IRAK exist in separate TRAF6 complexes. Co-immunoprecipitation, domain mapping, IL-1 stimulation, IKK and JNK activity assays Proceedings of the National Academy of Sciences of the United States of America Medium 10920205
2009 IL-1β stimulation induces interaction between MLK3 and TRAF6; RNAi knockdown of TRAF6 dramatically impairs MLK3 activation by IL-1β; TRAF6 promotes K63-linked ubiquitination of MLK3, which is important for MLK3 kinase activity. Co-immunoprecipitation, RNAi, in vitro kinase assays, K48/K63 ubiquitination assays Cellular signalling Medium 19586614
2017 Syntenin interacts with TRAF6 under basal conditions and dissociates upon IL-1 stimulation; IRAK1 overexpression competes with syntenin for TRAF6 binding; syntenin inhibits TRAF6 ubiquitination and acts as a physiological suppressor of IL-1R/TLR4-mediated NF-κB activation. Co-immunoprecipitation, NF-κB reporter assays, ubiquitination assays, syntenin knockdown Cellular signalling Medium 18234474
2019 BANK1 interacts with TRAF6 through five identified TRAF6-binding motifs in BANK1; the C-terminal domain of BANK1-FL and N-terminal domain of BANK1-Δ2 are required for TRAF6 binding; BANK1-TIR domain is important for K63-linked polyubiquitination and IL-8 production in B cell innate immune signaling. Co-immunoprecipitation, TRAF6-binding motif point mutations, decoy peptide experiments, K63-Ub assays, TLR7/9 stimulation Cellular & molecular immunology Medium 31243359
2024 TRAF6 stabilizes YAP1 via K63-linked polyubiquitination, promoting formation of the YAP1/TFCP2 transcriptional complex and subsequent PD-L1 transcription in melanoma cells; TRAF6 inhibition reduces membrane PD-L1 expression and enhances CD8+ T cell cytolytic activity. CRISPR interference screening, Co-immunoprecipitation, K63-ubiquitination assays, transcriptional reporter assays, in vivo tumor models Cancer letters Medium 38583649

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes & development 1022 10215628
2008 TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Molecular cell 479 18922473
2015 Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunological reviews 363 26085208
2003 TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. BioEssays : news and reviews in molecular, cellular and developmental biology 241 14579250
2010 The TAK1-TRAF6 signalling pathway. The international journal of biochemistry & cell biology 235 20060931
2003 TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 216 14499111
2018 YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. Circulation research 195 29794022
2010 Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice. The Journal of cell biology 186 21187332
2018 Inhibition of TRAF6 ubiquitin-ligase activity by PRDX1 leads to inhibition of NFKB activation and autophagy activation. Autophagy 183 29929436
2018 Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis. Journal of the American College of Cardiology 161 29406859
2011 TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer. Nature communications 148 21629263
2004 The role of TRAF6 in signal transduction and the immune response. Microbes and infection 121 15555541
2008 TRAF6 is a critical signal transducer in IL-33 signaling pathway. Cellular signalling 117 18603409
2004 TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6. Proceedings of the National Academy of Sciences of the United States of America 115 15492226
2017 Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling. Proceedings of the National Academy of Sciences of the United States of America 96 28404732
2012 Angiotensin II increases CTGF expression via MAPKs/TGF-β1/TRAF6 pathway in atrial fibroblasts. Experimental cell research 88 22749815
2008 TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. The Journal of biological chemistry 88 18984593
2013 TRAF6 upregulates expression of HIF-1α and promotes tumor angiogenesis. Cancer research 87 23722539
2018 Assembly mechanism of the CARMA1-BCL10-MALT1-TRAF6 signalosome. Proceedings of the National Academy of Sciences of the United States of America 86 29382759
2019 TRAF6 directs FOXP3 localization and facilitates regulatory T-cell function through K63-linked ubiquitination. The EMBO journal 84 30886050
2012 TWEAK and TRAF6 regulate skeletal muscle atrophy. Current opinion in clinical nutrition and metabolic care 84 22366923
2008 Herpesvirus tegument protein activates NF-kappaB signaling through the TRAF6 adaptor protein. Proceedings of the National Academy of Sciences of the United States of America 82 18682563
2014 miR-146a ameliorates liver ischemia/reperfusion injury by suppressing IRAK1 and TRAF6. PloS one 79 24987958
2014 EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis. The Journal of clinical investigation 75 25061874
2018 Roles of TRAF6 in Central Nervous System. Current neuropharmacology 70 29651950
2020 Luteolin alleviates neuroinflammation via downregulating the TLR4/TRAF6/NF-κB pathway after intracerebral hemorrhage. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 68 32114357
2016 Epigallocatechin-3-gallate(EGCG) suppresses melanoma cell growth and metastasis by targeting TRAF6 activity. Oncotarget 68 27791197
2022 USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction. Cell death & disease 67 35422093
2019 MicroRNA-125b protects liver from ischemia/reperfusion injury via inhibiting TRAF6 and NF-κB pathway. Bioscience, biotechnology, and biochemistry 67 30686117
2014 CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation. Cell research 66 24777252
2015 TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis. The Journal of clinical investigation 64 26619121
2013 SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria. Molecular biology of the cell 61 23885119
2007 Molecular basis for the unique specificity of TRAF6. Advances in experimental medicine and biology 61 17633022
2021 TNF receptor-associated factor 6 (TRAF6) plays crucial roles in multiple biological systems through polyubiquitination-mediated NF-κB activation. Proceedings of the Japan Academy. Series B, Physical and biological sciences 60 33840674
2015 Discovery of small molecule CD40-TRAF6 inhibitors. Journal of chemical information and modeling 56 25622654
2000 T6BP, a TRAF6-interacting protein involved in IL-1 signaling. Proceedings of the National Academy of Sciences of the United States of America 56 10920205
2016 SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer. Oncogene 53 27869166
2020 The relationship between TRAF6 and tumors. Cancer cell international 52 32905356
2019 GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia. Autophagy 51 30929559
2017 Regulation of MiR-146a and TRAF6 in the Diagnose of Lupus Nephritis. Medical science monitor : international medical journal of experimental and clinical research 50 28549054
2012 TRAF6 regulates proliferation, apoptosis, and invasion of osteosarcoma cell. Molecular and cellular biochemistry 49 22886393
2019 BANK1 interacts with TRAF6 and MyD88 in innate immune signaling in B cells. Cellular & molecular immunology 48 31243359
2016 TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin. Oncotarget 48 26769849
2004 The coiled-coil domain of TRAF6 is essential for its auto-ubiquitination. Biochemical and biophysical research communications 48 15465037
2020 Mechanism by which TRAF6 Participates in the Immune Regulation of Autoimmune Diseases and Cancer. BioMed research international 47 33294443
2018 miR-146a promotes cervical cancer cell viability via targeting IRAK1 and TRAF6. Oncology reports 47 29693168
2017 Inositol polyphosphate multikinase promotes Toll-like receptor-induced inflammation by stabilizing TRAF6. Science advances 46 28439546
2014 Isolation and characterization of tumor necrosis factor receptor-associated factor 6 (TRAF6) from grouper, Epinephelus tauvina. Fish & shellfish immunology 45 24811008
2020 Kaempferol attenuates streptozotocin-induced diabetic nephropathy by downregulating TRAF6 expression: The role of TRAF6 in diabetic nephropathy. Journal of ethnopharmacology 43 33152432
2022 DNMT1-mediated epigenetic silencing of TRAF6 promotes prostate cancer tumorigenesis and metastasis by enhancing EZH2 stability. Oncogene 41 35804015
2020 SNHG16/miR-605-3p/TRAF6/NF-κB feedback loop regulates hepatocellular carcinoma metastasis. Journal of cellular and molecular medicine 40 32436333
2019 Ubiquitination of cGAS by TRAF6 regulates anti-DNA viral innate immune responses. Biochemical and biophysical research communications 40 31078259
2018 Mechanism of ubiquitin transfer promoted by TRAF6. Proceedings of the National Academy of Sciences of the United States of America 39 29432170
2015 Toxoplasma gondii GRA7-Induced TRAF6 Activation Contributes to Host Protective Immunity. Infection and immunity 38 26553469
2021 OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways. Hepatology (Baltimore, Md.) 36 34591986
2017 Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3. The Biochemical journal 36 28507161
2017 Hepatoprotective effect of quercetin via TRAF6/JNK pathway in acute hepatitis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 29174851
2021 A20 Establishes Negative Feedback With TRAF6/NF-κB and Attenuates Early Brain Injury After Experimental Subarachnoid Hemorrhage. Frontiers in immunology 35 34381441
2018 Molecular cloning and functional characterization of TRAF6 and TAK1 in rainbow trout, Oncorhynchus mykiss. Fish & shellfish immunology 35 30391533
2016 K63-Ubiquitylation and TRAF6 Pathways Regulate Mammalian P-Body Formation and mRNA Decapping. Molecular cell 35 27315556
2009 Cytokine-induced activation of mixed lineage kinase 3 requires TRAF2 and TRAF6. Cellular signalling 35 19586614
2017 Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation. Journal of neuroinflammation 33 28494768
2012 Expression of TRAF6 and ubiquitin mRNA in skeletal muscle of gastric cancer patients. Journal of experimental & clinical cancer research : CR 33 23013936
2007 Roles of TRAF6 in CD40 signaling. Immunologic research 32 17917059
2020 Sirt1-ROS-TRAF6 Signaling-Induced Pyroptosis Contributes to Early Injury in Ischemic Mice. Neuroscience bulletin 31 32253651
2017 Functional diversity of miR-146a-5p and TRAF6 in normal and oral cancer cells. International journal of oncology 30 29048658
2010 NUMBL interacts with TRAF6 and promotes the degradation of TRAF6. Biochemical and biophysical research communications 30 20079715
2010 Glutaredoxin-1 regulates TRAF6 activation and the IL-1 receptor/TLR4 signalling. Biochemical and biophysical research communications 30 21078302
2016 Relationship between TRAF6 and deterioration of HCC: an immunohistochemical and in vitro study. Cancer cell international 29 27708550
2008 TRAF6 deficiency promotes TNF-induced cell death through inactivation of GSK3beta. Cell death and differentiation 29 18202703
2024 Enhanced NF-κB activation via HIV-1 Tat-TRAF6 cross-talk. Science advances 28 38241362
2023 Sufu limits sepsis-induced lung inflammation via regulating phase separation of TRAF6. Theranostics 27 37441604
2019 Sodium butyrate-activated TRAF6-TXNIP pathway affects A549 cells proliferation and migration. Cancer medicine 26 31578830
2017 miR‑146b‑5p suppresses glioblastoma cell resistance to temozolomide through targeting TRAF6. Oncology reports 26 29048680
2023 Rnd3 suppresses endothelial cell pyroptosis in atherosclerosis through regulation of ubiquitination of TRAF6. Clinical and translational medicine 24 37743632
2022 TRAF6 regulates the signaling pathway influencing colorectal cancer function through ubiquitination mechanisms. Cancer science 24 35179811
2016 Cutting Edge: A Cullin-5-TRAF6 Interaction Promotes TRAF6 Polyubiquitination and Lipopolysaccharide Signaling. Journal of immunology (Baltimore, Md. : 1950) 24 27233966
2020 NPM1 mutant maintains ULK1 protein stability via TRAF6-dependent ubiquitination to promote autophagic cell survival in leukemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 33201521
2019 TRAF6 mediates human DNA2 polyubiquitination and nuclear localization to maintain nuclear genome integrity. Nucleic acids research 23 31216032
2018 TRAF6 regulates EGF-induced cell transformation and cSCC malignant phenotype through CD147/EGFR. Oncogenesis 23 29463844
2017 SMN1 functions as a novel inhibitor for TRAF6-mediated NF-κB signaling. Biochimica et biophysica acta. Molecular cell research 23 28214532
2016 MicroRNA-146a Contributes to SCI Recovery via Regulating TRAF6 and IRAK1 Expression. BioMed research international 23 27830143
2024 TRAF6 enhances PD-L1 expression through YAP1-TFCP2 signaling in melanoma. Cancer letters 22 38583649
2023 USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses. International immunopharmacology 22 37657242
2014 Molecular characterization and functional analysis of duck TRAF6. Developmental and comparative immunology 22 25445905
2013 TRAF6 promoted the tumorigenicity of esophageal squamous cell carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 23794111
2007 Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling. Cellular signalling 22 18234474
2018 TRAF6 interacts with and ubiquitinates PIK3CA to enhance PI3K activation. FEBS letters 21 29729098
2017 A Dithiol Compound Binds to the Zinc Finger Protein TRAF6 and Suppresses Its Ubiquitination. ChemMedChem 21 28884970
2023 USP7 Inhibits Osteoclastogenesis via Dual Effects of Attenuating TRAF6/TAK1 Axis and Stimulating STING Signaling. Aging and disease 20 37199589
2020 Destablilization of TRAF6 by DRAK1 Suppresses Tumor Growth and Metastasis in Cervical Cancer Cells. Cancer research 20 32265222
2024 Desulfovibrio vulgaris flagellin exacerbates colorectal cancer through activating LRRC19/TRAF6/TAK1 pathway. Gut microbes 19 39718561
2023 CD4+ T-Cell Legumain Deficiency Attenuates Hypertensive Damage via Preservation of TRAF6. Circulation research 19 38047378
2022 miR-146a contributes to atherosclerotic plaque stability by regulating the expression of TRAF6 and IRAK-1. Molecular biology reports 19 35195809
2021 TRAF6 Contributes to CFA-Induced Spinal Microglial Activation and Chronic Inflammatory Pain in Mice. Cellular and molecular neurobiology 19 33694132
2005 TRAF6 and Src kinase activity regulates Cot activation by IL-1. Cellular signalling 19 16371247
2018 The effects of TRAF6 on proliferation, apoptosis and invasion in osteosarcoma are regulated by miR-124. International journal of molecular medicine 18 29436576
2018 RSK2 is required for TRAF6 phosphorylation-mediated colon inflammation. Oncogene 18 29563609
2013 TRAF6 promoted the metastasis of esophageal squamous cell carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 18 24026882
2020 TRAF6 Promotes Gastric Cancer Cell Self-Renewal, Proliferation, and Migration. Stem cells international 17 32724313