Affinage

TRAF6

TNF receptor-associated factor 6 · UniProt Q9Y4K3

Length
522 aa
Mass
59.6 kDa
Annotated
2026-06-10
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAF6 is a RING-domain E3 ubiquitin ligase and signaling adaptor that operates downstream of a broad set of receptors—IL-1R/TLR, CD40, TNF receptor superfamily members, and TGF-β receptors—to translate receptor engagement into NF-κB, JNK, and p38 MAPK activation, with knockout animals exhibiting osteopetrosis, defective osteoclast function, and impaired innate and adaptive immune responses (PMID:10215628, PMID:14499111, PMID:12060722, PMID:18922473). Its core catalytic activity is synthesis of K63-linked polyubiquitin chains via a RING dimer that uses a concerted allosteric mechanism, cooperating with the Ubc13–Uev1A E2 to build chains both on itself (auto-ubiquitination) and on substrates (PMID:15492226, PMID:29432170). Higher-order assembly is central to TRAF6 function: oligomerization-promoting partners such as TIFA drive auto-polyubiquitination and IKK activation, and TRAF6 undergoes liquid–liquid phase separation during LPS-induced inflammation that is required for ubiquitination-driven NF-κB activation (PMID:15492226, PMID:37441604). These K63-Ub products engage the TAK1 complex (and, in some viral pathways, MEKK1) and feed downstream kinase modules; TRAF6 also carries E3 ligase-independent scaffolding roles, since Pellino1/2 generate redundant K63-Ub chains and catalytically inactive TRAF6 partially restores IL-1 signaling (PMID:18922473, PMID:28404732, PMID:18984593, PMID:28507161). Beyond canonical immune signaling, TRAF6 K63-ubiquitinates a diverse substrate set to control protein stability, localization, or activity—including HIF-1α stabilization for tumor angiogenesis, PINK1 for mitophagy, FOXP3 for Treg nuclear localization and suppressive function, ULK1 and BECN1 for autophagy, hDNA2 for DNA end resection and homology-directed repair, and YAP1 for PD-L1 transcription (PMID:23722539, PMID:23885119, PMID:30886050, PMID:31216032, PMID:30929559, PMID:38583649). TRAF6 additionally drives muscle satellite cell regeneration through an ERK/JNK→c-JUN→Pax7 axis (PMID:26619121). Its activity is tightly tuned by post-translational modification—deglutathionylation by GRX-1, neddylation at Lys124, and RSK2 phosphorylation all enhance K63 auto-ubiquitination—and by numerous binding partners that act as positive (TIFA, Cullin-5, viperin, GCA) or negative (PRDX1, OTUB1, SMN1, syntenin, Sufu, NUMBL, YAP) regulators (PMID:21078302, PMID:30626891, PMID:29563609, PMID:15492226, PMID:27233966, PMID:33779167, PMID:30929559, PMID:29929436, PMID:34591986, PMID:28214532, PMID:18234474, PMID:37441604, PMID:20079715, PMID:29794022).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 High

    Established that TRAF6 is an essential, non-redundant in vivo signaling mediator shared across IL-1, CD40, and LPS pathways, linking it to both immunity and bone homeostasis.

    Evidence TRAF6 knockout mice with osteoclast and multi-pathway signaling assays

    PMID:10215628

    Open questions at the time
    • Did not define the molecular activity of TRAF6
    • Mechanism connecting TRAF6 to each receptor not resolved
  2. 2002 High

    Defined receptor selectivity by showing TRAF6 associates with XEDAR and TROY/TAJ but not EDAR, connecting it to epidermal appendage development through NF-κB.

    Evidence Co-IP, TRAF6-deficient mice, NF-κB reporter assays

    PMID:12060722

    Open questions at the time
    • Structural basis of receptor discrimination unresolved
    • Downstream substrates in this pathway not identified
  3. 2003 High

    Extended TRAF6 function to dendritic cell maturation and adaptive immune priming, showing it is required for DC antigen-presentation capacity and a specific splenic DC subset.

    Evidence TRAF6-deficient mice and bone marrow chimeras with flow cytometry/functional assays

    PMID:14499111

    Open questions at the time
    • Substrates driving DC maturation not defined
  4. 2004 High

    Reconstituted the core enzymatic mechanism, showing oligomerization (driven by TIFA) triggers TRAF6 K63 auto-polyubiquitination and IKK activation using purified TRAF6, TAK1 complex, and Ubc13-Uev1A.

    Evidence In vitro reconstitution with purified proteins and cell-free IKK activation assay

    PMID:15492226

    Open questions at the time
    • Did not resolve atomic RING-domain catalytic geometry
    • Physiological oligomerization triggers beyond TIFA not enumerated here
  5. 2008 High

    Broadened the pathway repertoire by showing TRAF6 mediates TGF-β-induced Smad-independent JNK/p38 activation and RIG-I/MDA5 antiviral signaling, the latter using MEKK1 rather than TAK1 as the MAP3K.

    Evidence Co-IP, siRNA, ubiquitination and kinase assays; TRAF6/TAK1-deficient MEFs with MEKK1 rescue

    PMID:18922473 PMID:18984593

    Open questions at the time
    • How MAP3K choice (TAK1 vs MEKK1) is determined unresolved
  6. 2008 Medium

    Showed TRAF6 protects against cell death, with its loss causing ROS accumulation, sustained JNK, and GSK3β inactivation downstream of TNF.

    Evidence TRAF6-KO 3T3 cells with ROS/kinase assays and constitutively active GSK3β rescue

    PMID:18202703

    Open questions at the time
    • Direct substrate linking TRAF6 to GSK3β regulation not identified
  7. 2013 Medium

    Demonstrated that TRAF6 K63-ubiquitination controls substrate stability and localization beyond signaling kinases, stabilizing HIF-1α (angiogenesis) and PINK1 on depolarized mitochondria (mitophagy/parkin recruitment).

    Evidence Co-IP, site-specific ubiquitination assays, E3-deficient mutant, fractionation, imaging

    PMID:23722539 PMID:23885119

    Open questions at the time
    • Cellular signals routing TRAF6 to these non-canonical substrates not defined
    • PINK1 work medium-supported by single lab
  8. 2016 Medium

    Expanded the substrate landscape to invasion/metastasis (Basigin membrane recruitment) and to mRNA decapping/P-body formation via DCP1a, indicating roles in cancer cell behavior and RNA metabolism.

    Evidence Co-IP, ubiquitination assays, mutagenesis, invasion/metastasis and mRNA decay assays

    PMID:26769849 PMID:27315556

    Open questions at the time
    • Direct vs indirect ubiquitination of DCP1a not fully resolved
    • Single-lab support for each substrate
  9. 2017 High

    Dissected catalytic versus scaffolding contributions, showing Pellino1/2 redundantly generate K63 chains and that E3-inactive TRAF6 retains partial IL-1 signaling, while TRAF6 also enables an alternative TAB1-TAK1 pathway requiring its E3 activity.

    Evidence CRISPR triple-KO cells, E3-inactive knockin mice, TAB2/3 DKO/TKO cells with rescue and TAK1 assays

    PMID:28404732 PMID:28507161

    Open questions at the time
    • Which signaling outputs are E3-dependent vs scaffold-dependent not comprehensively mapped
  10. 2018 High

    Resolved the catalytic mechanism and supramolecular assembly: a concerted allosteric RING dimer mediates Ub transfer, and TRAF6 cooperatively decorates BCL10 filaments within the CBM signalosome.

    Evidence Structural modeling/mutagenesis of RING extensions; cryo-EM of BCL10 CARD filament with imaging and reconstitution

    PMID:29382759 PMID:29432170

    Open questions at the time
    • Full atomic structure of an active TRAF6-E2-substrate complex not determined
    • How filament geometry tunes chain length unresolved
  11. 2019 High

    Established TRAF6 as a regulator of Treg function (FOXP3 nuclear localization), DNA repair (hDNA2 resection), autophagy (ULK1), and additional immune substrates, while implicating it in tumor immune evasion.

    Evidence Conditional KO mice, site-specific ubiquitination mutants, fractionation, DNA-repair, autophagy and tumor assays

    PMID:30886050 PMID:30929559 PMID:31216032

    Open questions at the time
    • How substrate selection is partitioned across cellular compartments unclear
    • ULK1/hDNA2 findings medium-supported single-lab
  12. 2019 Medium

    Defined an extensive layer of post-translational and partner regulation—neddylation at Lys124, RSK2 phosphorylation, and viperin/GCA-mediated activation—that tunes TRAF6 K63 ubiquitination output.

    Evidence Site-directed mutagenesis, neddylation/kinase/ubiquitination assays, KO mice, in vitro reconstitution

    PMID:29563609 PMID:30626891 PMID:33779167

    Open questions at the time
    • Interplay among the different PTMs on a single TRAF6 molecule not integrated
    • Crosstalk hierarchy among activators not established
  13. 2021 High

    Revealed bidirectional roles in T cell homeostasis—positive scaffolding for NF-κB and negative restraint of basal MALT1 protease—and identified deubiquitinase brakes (OTUB1) controlling TRAF6 in metabolic disease.

    Evidence Genetic mouse models, biochemical analyses, pharmacological MALT1 rescue; IP-MS/Co-IP, ubiquitination assays, NASH models

    PMID:34591986 PMID:34767456

    Open questions at the time
    • Molecular basis of TRAF6 suppression of MALT1 protease not fully defined
  14. 2023 High

    Showed phase separation of TRAF6 is essential for ubiquitination-driven NF-κB activation, and that Sufu and Rnd3 negatively regulate oligomerization/condensate formation and K63 vs K48 chain balance.

    Evidence In vitro phase separation with purified proteins, FRAP, Native-PAGE, Co-IP, in vivo lung-injury/pyroptosis models

    PMID:37441604 PMID:37743632

    Open questions at the time
    • Determinants of condensate composition and substrate enrichment unresolved
    • Link between condensate state and chain-linkage choice unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRAF6 achieves substrate specificity and the appropriate K63-chain output across its very broad substrate range—and how its compartmentalization, condensate state, and competing positive/negative regulators are integrated in a single cell—remains unresolved.
  • No unifying model of substrate selection
  • Quantitative integration of activators and DUBs/inhibitors lacking
  • Tissue-specific substrate priorities not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 3 R-HSA-73894 DNA Repair 1
Partners
BCL10CULLIN-5OTUB1PRDX1RSK2TAK1TIFAYAP1
Complex memberships
CBM (CARMA1-BCL10-MALT1) signalosomePINK1-SARM1-TRAF6 complexTAK1 (TAB1/TAB2/TAB3) complex

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TRAF6 knockout mice are osteopetrotic with impaired osteoclast function and show defective IL-1, CD40, and LPS signaling, establishing TRAF6 as an essential signaling mediator downstream of these diverse receptor pathways in vivo. Gene knockout mouse model with in vitro signaling assays Genes & development High 10215628
2003 TRAF6 is required for dendritic cell maturation; TRAF6-deficient DCs fail to upregulate MHCII and B7.2, produce inflammatory cytokines, or stimulate naive T cells in response to LPS or CD40L, and the CD4+CD8α− splenic DC subset is nearly absent. TRAF6-deficient mice and bone marrow chimeras; flow cytometry and functional assays Immunity High 14499111
2002 TRAF6 associates with XEDAR and TROY/TAJ (EDAR-related TNFR superfamily members) and is essential for XEDAR-mediated NF-κB activation, contributing to development of epidermal appendages; TRAF6 does not associate with EDAR. Co-immunoprecipitation; TRAF6-deficient mice; NF-κB reporter assays Proceedings of the National Academy of Sciences of the United States of America High 12060722
2008 TRAF6 is specifically required for TGF-β-induced, Smad-independent activation of JNK and p38; its C-terminal TRAF homology domain interacts with TGF-β receptors; TGF-β induces K63-linked ubiquitination of TRAF6 and promotes TRAF6–TAK1 association. Co-immunoprecipitation; siRNA knockdown; ubiquitination assays; kinase activation assays Molecular cell High 18922473
2004 TIFA (TRAF-interacting protein with a forkhead-associated domain) activates IKK by promoting oligomerization and K63-linked polyubiquitination of TRAF6; only oligomeric TIFA activates IKK; activation was reconstituted in vitro with purified TRAF6, TAK1 complex, and Ubc13-Uev1A. In vitro reconstitution with purified proteins; cell-free IKK activation assay; ubiquitination assay Proceedings of the National Academy of Sciences of the United States of America High 15492226
2011 TRAF6 associates with TβRI and mediates Lys63-linked polyubiquitination of TβRI, promoting PKCζ-dependent cleavage by TACE; the released TβRI intracellular domain translocates to the nucleus and, with p300, activates invasion-promoting genes (Snail, MMP2). Co-immunoprecipitation; ubiquitination assays; pharmacological inhibition; nuclear fractionation; cell invasion assays Nature communications High 21629263
2017 TRAF6 E3 ligase activity contributes to but is not solely essential for IL-1-dependent K63-Ub chain formation and TAK1 activation, because Pellino1/2 generate redundant K63-Ub chains; TRAF6/Pellino1/Pellino2 triple-KO abolishes K63-Ub formation on IRAK1, IRAK4, and MyD88. E3 ligase-inactive TRAF6 mutants partially restore IL-1 signaling, demonstrating E3 ligase-independent roles of TRAF6. CRISPR/Cas9 triple-KO cells; E3 ligase-inactive knockin mice (TRAF6[L74H]); ubiquitination assays; in vitro TAK1 activation assay Proceedings of the National Academy of Sciences of the United States of America High 28404732
2018 The TRAF6 RING dimer employs a concerted allosteric mechanism for ubiquitin transfer: both subunits cooperate, with the C-terminal extension of one TRAF6 RING subunit making trans-interactions with donor-Ub to promote Ub transfer to the E2. Structural modeling; biochemical ubiquitination assays; mutagenesis of RING domain extensions Proceedings of the National Academy of Sciences of the United States of America High 29432170
2018 The CBM (CARMA1-BCL10-MALT1) signalosome recruits TRAF6, which cooperatively decorates BCL10 filaments to form higher-order assemblies; cryo-EM structure of BCL10 CARD filament at 4.0-Å resolution redefines CARD-CARD interactions; MALT1 immediately dimerizes on the BCL10 filamentous scaffold before recruiting TRAF6. Cryo-electron microscopy; time-lapse confocal imaging; biochemical reconstitution Proceedings of the National Academy of Sciences of the United States of America High 29382759
2018 PRDX1 interacts with the RING finger domain of TRAF6 and inhibits its E3 ubiquitin ligase activity, thereby suppressing K63-linked ubiquitination of ECSIT (required for NF-κB activation) and BECN1 (required for autophagy) in response to TLR4 stimulation. Co-immunoprecipitation; in vitro ubiquitination assay; siRNA knockdown (PRDX1KD cells); NF-κB reporter assay Autophagy High 29929436
2013 TRAF6 binds HIF-1α and mediates its K63-linked polyubiquitination, increasing HIF-1α protein stability independent of oxygen levels; TRAF6 E3 ligase activity is required for this effect and for promoting tumor angiogenesis. Co-immunoprecipitation; ubiquitination assay; E3 ligase-deficient mutant; cell-based HIF-1α protein stability assay; in vivo tumor angiogenesis assay Cancer research Medium 23722539
2013 PINK1 forms a complex with SARM1 and TRAF6; TRAF6 mediates K63-linked ubiquitination of PINK1 at Lys433, promoted by SARM1; this complex is required for PINK1 stabilization on depolarized mitochondria and subsequent parkin recruitment for mitophagy; some pathogenic PINK1 mutations reduce complex formation and ubiquitination. Co-immunoprecipitation; ubiquitination assay with Lys433 mutant; siRNA knockdown; mitochondrial fractionation; fluorescence microscopy of parkin recruitment Molecular biology of the cell High 23885119
2008 TRAF6 is required for RIG-I/MDA5 pathway-dependent NF-κB, JNK, and p38 activation in response to viral infection or poly(I:C); TRAF6-deficient MEFs show impaired IRF3-independent signaling. MEKK1 (not TAK1) is the MAP3K used by TRAF6 for IFN-β induction in this pathway; forced MEKK1 + IRF3 expression induces IFN-β. TRAF6-deficient MEFs; TAK1-deficient MEFs; siRNA knockdown of MEKK1; overexpression rescue; IFN-β reporter assay The Journal of biological chemistry High 18984593
2019 TRAF6 mediates K63-linked ubiquitination of FOXP3 at Lys262, directing its proper nuclear localization; loss of TRAF6 or mutation of K262 causes perinuclear accumulation of FOXP3 and disrupted Treg suppressive function; Treg-specific TRAF6 deletion renders mice resistant to implanted tumors. Treg-specific TRAF6 conditional KO mice; site-directed mutagenesis (K262R FOXP3); ubiquitination assay; immunofluorescence localization; in vivo tumor models The EMBO journal High 30886050
2008 HSV-1 UL37 tegument protein activates NF-κB through direct interaction with TRAF6 via a TRAF6-binding domain in UL37; mutation of this domain reduces NF-κB activation during early infection. Co-immunoprecipitation; NF-κB reporter assay; recombinant virus with mutated TRAF6-binding site Proceedings of the National Academy of Sciences of the United States of America Medium 18682563
2000 T6BP specifically associates with TRAF6 via the coiled-coil region of T6BP and the N-terminal RING/zinc finger domains of TRAF6; IL-1 (not TNF) induces TRAF6–T6BP complex formation in an IRAK-dependent manner; IRAK is not present in TRAF6–T6BP complexes. Co-immunoprecipitation; yeast two-hybrid; domain-mapping pulldowns; IL-1 stimulation time course Proceedings of the National Academy of Sciences of the United States of America Medium 10920205
2010 The RING finger motif of TRAF6 is S-glutathionylated under basal conditions; upon IL-1 stimulation, GRX-1 catalyzes deglutathionylation of TRAF6, which is essential for TRAF6 K63-linked auto-polyubiquitination and subsequent NF-κB activation; GRX-1 knockdown severely reduces IL-1R/TLR4-mediated NF-κB induction. RNAi knockdown; S-glutathionylation detection assay; ubiquitination assay; NF-κB reporter assay Biochemical and biophysical research communications Medium 21078302
2013 p62/sequestosome-1 interacts with NEMO and is required for TRAF6-mediated K63-linked ubiquitination of NEMO; p62 depletion abolishes TRAF6's ability to ubiquitinate NEMO and severely impairs NF-κB activation following IL-1β stimulation. Co-immunoprecipitation; siRNA knockdown; ubiquitination assay; NF-κB activation assay Molecular immunology Medium 24270048
2016 TRAF6 interacts with Basigin (BSG/CD147) and mediates its K63-linked ubiquitination, promoting BSG recruitment to the plasma membrane and BSG-dependent MMP9 induction; TRAF6 depletion reduces BSG membrane localization and impairs melanoma invasion/metastasis. Co-immunoprecipitation; shRNA knockdown; ubiquitination assay; cell invasion assays; in vivo metastasis model Oncotarget Medium 26769849
2010 NUMBL directly binds TRAF6 in vivo and in vitro, promotes K48-linked (but not K63-linked) polyubiquitination of TRAF6, reduces TRAF6 protein half-life, and thereby inhibits NF-κB signaling; NUMBL knockdown increases endogenous TRAF6 protein in neurons. Co-immunoprecipitation; in vivo ubiquitination assay with K48 and K63 mutants; siRNA knockdown; pulse-chase protein stability assay Biochemical and biophysical research communications Medium 20079715
2017 IL-1β can activate a TAB1-TAK1 heterodimer in the absence of TAB2/TAB3, but this alternative pathway requires TRAF6 expression and E3 ligase activity and depends on Ubc13-directed K63-Ub chain formation; in TAB2/3 DKO cells, IL-1β signaling is transient and JNK1/2 and p38γ activation is greatly reduced. TAB2/3 double-KO and triple-KO cell lines; TRAF6 siRNA; re-expression rescue with TAB1, TAB2, or ubiquitin-binding-defective TAB2; kinase assays The Biochemical journal High 28507161
2019 TRAF6 K63-linked ubiquitinates cGAS, activating its enzymatic activity; TRAF6 knockdown decreases cGAS-induced IFNβ production upon HSV-1 infection. Ectopic expression and knockdown; ubiquitination assay; IFNβ reporter/expression assay; HSV-1 infection Biochemical and biophysical research communications Low 31078259
2019 TRAF6 binds and K63-ubiquitinates hDNA2, increasing its stability and promoting its nuclear localization; TRAF6-mediated polyubiquitination of hDNA2 is required for DNA end resection and homology-directed repair; inhibiting this ubiquitination abolishes nuclear hDNA2 localization. Co-immunoprecipitation; ubiquitination assay; nuclear fractionation; DNA end resection assay; HDR assay Nucleic acids research Medium 31216032
2016 K63-linked ubiquitin chains and the E3 ligase TRAF6 regulate mammalian P-body formation and mRNA decapping; TRAF6 binds DCP1a and indirectly regulates its phosphorylation; mutation of six C-terminal lysines of DCP1a suppresses decapping activity and impairs interaction with DCP2, EDC4, and XRN1. Co-immunoprecipitation; DCP1a lysine-mutant analysis; P-body formation imaging; mRNA decay assays; ubiquitination assays Molecular cell Medium 27315556
2009 IL-1β stimulates a TRAF6–MLK3 interaction; TRAF6 RNAi dramatically impairs MLK3 kinase activation by IL-1β; TNF/IL-1β also stimulates K63-linked ubiquitination of MLK3 that is important for its kinase activity, while K48-linked ubiquitination directs MLK3 for proteasomal degradation. Co-immunoprecipitation; RNAi; in vitro kinase assay; linkage-specific ubiquitination analysis Cellular signalling Medium 19586614
2019 GCA (grancalcin) activates TRAF6 ubiquitin ligase activity to induce K63-linked ubiquitination of ULK1, resulting in ULK1 stabilization and activation and consequent autophagy induction; this GCA-TRAF6-ULK1 axis mediates imatinib resistance in CML. Co-immunoprecipitation; ubiquitination assay; siRNA/overexpression; autophagy flux assays; drug resistance assays Autophagy Medium 30929559
2021 TRAF6 acts as both a positive regulator (scaffolding for NF-κB activation) and a negative regulator (suppressor of basal MALT1 protease activity) in T cells; loss of TRAF6-mediated homeostatic suppression of MALT1 protease leads to severe autoimmune inflammation fully reverted by genetic or pharmacological MALT1 protease inactivation. Genetically engineered mouse models; biochemical analyses; pharmacological MALT1 inhibition; epistasis experiments Science immunology High 34767456
2016 Cullin-5 (Cul-5) directly binds TRAF6 (C-terminal domain of Cul-5 interacts with TRAF-C domain of TRAF6) and promotes TRAF6 K63-linked polyubiquitination in response to LPS; hemizygous Cul-5 KO delays NF-κB and MAPK activation in LPS-stimulated macrophages. Co-immunoprecipitation; domain-mapping pulldown; ubiquitination assay; hemizygous KO mice; macrophage signaling assays Journal of immunology Medium 27233966
2018 RSK2 directly phosphorylates TRAF6 at Ser46, Ser47, and Ser48 (in vitro kinase assay); RSK2 positively regulates TRAF6 K63-linked ubiquitination; TRAF6 is also required for RSK2 ubiquitination; RSK2 KO mice show reduced TRAF6 K63-ubiquitination and attenuated colon inflammation. In vitro kinase assay; Co-immunoprecipitation; ubiquitination assay; RSK2 KO mice; colon inflammation model Oncogene High 29563609
2019 TRAF6 directly interacts with PIK3CA (p110α catalytic subunit of PI3K) and promotes its non-proteolytic K63-linked polyubiquitination under serum stimulation; TRAF6 overexpression enhances PI3K activation and downstream AKT phosphorylation and cell growth. Co-immunoprecipitation; ubiquitination assay; overexpression/knockdown; AKT phosphorylation assay; cell growth assay FEBS letters Medium 29729098
2019 HIV-1 Tat directly interacts with TRAF6, increases TRAF6 oligomerization and auto-ubiquitination, and promotes K63-linked polyubiquitin chain synthesis, thereby activating NF-κB and HIV-1 transcription; TRAF6 knockdown inhibits HIV-1 transcription. Co-immunoprecipitation; ubiquitination assay; TRAF6 KD/overexpression; NF-κB reporter and HIV-1 transcription assays Science advances Medium 38241362
2010 TRAF6 binds the IL-2Rβ chain at a site overlapping the Jak1-binding site and negatively regulates IL-2-induced Jak1-Erk pathway activation; a β-chain mutation that inactivates TRAF6 binding but retains Jak1 binding abrogates TRAF6-dependent suppression of IL-2 signaling; Traf6−/− CD4+ T cells show hyperactivated IL-2 signaling. Traf6−/− mouse T cells and MEFs; β-chain binding-site mutants; IL-2 stimulation assays; Jak1 and Erk activation assays Genes to cells : devoted to molecular & cellular mechanisms Medium 21155952
2015 Satellite cell-specific deletion of Traf6 causes profound muscle regeneration defects with reduced PAX7 and late myogenesis markers; TRAF6 activates ERK1/2 and JNK1/2 → c-JUN → Pax7 promoter binding, augmenting Pax7 expression; TRAF6/c-JUN signaling also represses miR-1 and miR-206 to maintain PAX7 levels. Conditional (satellite cell-specific) KO mice; ChIP (c-JUN at Pax7 promoter); miRNA expression analysis; kinase activation assays; mdx double-mutant model The Journal of clinical investigation High 26619121
2021 OTUB1 directly binds TRAF6 and suppresses its K63-linked polyubiquitination, thereby inhibiting TRAF6-mediated activation of ASK1 and downstream pathways; OTUB1 KO aggravates NASH, and hepatocyte-specific OTUB1 overexpression alleviates it. Immunoprecipitation-mass spectrometry; Co-immunoprecipitation; ubiquitination assay; OTUB1 KO and overexpression mouse models; NASH diet models Hepatology Medium 34591986
2023 TRAF6 undergoes phase separation (liquid-liquid condensate/droplet formation) during LPS-induced inflammation, which is essential for its ubiquitination-mediated NF-κB activation; Sufu directly interacts with TRAF6, prevents its oligomerization and autoubiquitination, and inhibits TRAF6 phase-separated droplet formation; Sufu deletion augments LPS/CLP-induced lung injury and is rescued by TRAF6 depletion. Co-immunoprecipitation; FRAP; Native-PAGE; in vitro phase separation assay with purified proteins; GFP-TRAF6 stable cell line; CLP sepsis mouse model Theranostics High 37441604
2020 TRAF6 mediates K63-linked ubiquitination of STAT6, promoting STAT6 protein stability by reducing its K48-linked ubiquitination (degradation); TRAF6's E3 ligase activity is dispensable for STAT6 stabilization despite promoting K63-ubiquitination; TRAF6 deficiency impairs IL-4-induced M2 macrophage gene expression. Co-immunoprecipitation; overexpression/knockdown/KO; ubiquitination assays (K48/K63 specific); STAT6 stability assay Molecular immunology Medium 33017719
2021 Viperin binds TRAF6 and activates its ubiquitin transfer activity 2.5-fold, causing increased polyubiquitinated forms of TRAF6 important for immune signaling. Protein-protein binding assay; in vitro ubiquitin transfer assay with purified proteins Journal of the American Chemical Society Medium 33779167
2019 BANK1 interacts with TRAF6 via its TIR domain and via five identified TRAF6-binding motifs; the C-terminal domain of BANK1-FL and N-terminal domain of BANK1-Δ2 are required for TRAF6 binding; BANK1 Δ2 isoform lacking TIR domain shows enhanced K63-linked polyubiquitination and IL-8 production. Co-immunoprecipitation; point mutation and decoy peptide analysis; K63-ubiquitination assay; IL-8 production assay Cellular & molecular immunology Medium 31243359
2019 TRAF6 neddylation at Lys124 is essential for IL-17A-induced NF-κB activation in fibroblast-like synoviocytes; K124R mutation markedly impairs NEDD8 conjugation to TRAF6 and attenuates IL-17A-induced NF-κB activity. Site-directed mutagenesis (K124R); neddylation assay; NF-κB activation assay; collagen-induced arthritis mouse model Laboratory investigation Medium 30626891
2018 YAP interacts with TRAF6 (E3 ligase), promotes TRAF6 ubiquitination and degradation, inhibiting NF-κB activation in endothelial cells; endothelial YAP KO augments inflammatory response reversed by TRAF6 depletion. Co-immunoprecipitation; ubiquitination assay; endothelial-specific YAP and TRAF6 KO mice; sepsis/LPS models Circulation research High 29794022
2007 Syntenin specifically interacts with TRAF6 under physiological conditions and inhibits TRAF6-induced NF-κB and AP-1 activation; upon IL-1 stimulation, syntenin dissociates from TRAF6 as IRAK1 overexpression competes for TRAF6 binding and restores TRAF6 ubiquitination; syntenin knockdown potentiates IL-1/LPS-triggered NF-κB activation. Co-immunoprecipitation; NF-κB/AP-1 reporter assays; siRNA knockdown; competition binding assay Cellular signalling Medium 18234474
2017 SMN1 physically interacts with TRAF6 and with IKK-α, IKK-β, and IKK-γ; SMN1 inhibits TRAF6 E3 ubiquitin ligase activity and IKK kinase activity; SMN1 depletion enhances IL-1β-induced IKK activation and inflammatory mediator production; SMA patient fibroblasts show potentiated IL-1β-induced IKK activity. Co-immunoprecipitation; in vitro E3 ligase activity assay; in vitro IKK kinase assay; siRNA knockdown; patient fibroblasts Biochimica et biophysica acta. Molecular cell research Medium 28214532
2008 TRAF6 deficiency in TNF signaling leads to ROS accumulation, prolonged JNK activation, reduced NF-κB p65 phosphorylation, and accelerated cell death; TRAF6 deficiency causes constitutive phosphorylation (inactivation) of GSK3β; restoration of GSK3β activity rescues cell death in TRAF6-null cells. TRAF6-KO 3T3 cells; ROS measurement; JNK/NF-κB activation assays; GSK3β kinase assay; constitutively active GSK3β rescue Cell death and differentiation Medium 18202703
2022 USP15 interacts with BECN1 (but not with TRAF6) and induces deubiquitination of BECN1, attenuating TRAF6-BECN1 axis-dependent autophagy induction and lung cancer migration/invasion. Co-immunoprecipitation; deubiquitination assay; CRISPR-KO cell lines; migration/invasion assays Cell death & disease Medium 35422093
2024 TRAF6 stabilizes YAP1 via K63-linked polyubiquitination, which promotes formation of YAP1/TFCP2 transcriptional complex and PD-L1 transcription in melanoma; TRAF6 inhibition with Bortezomib reduces endogenous PD-L1 and enhances CD8+ T cell cytolytic activity. CRISPR interference screening; Co-immunoprecipitation; K63-ubiquitination assay; in vitro and in vivo functional assays; flow cytometry Cancer letters Medium 38583649
2003 c-Src interacts with TRAF6 in response to IL-1 and this interaction is required for c-Src activity; TRAF6 and c-Src synergistically activate AP-1 through the PI3K-AKT-JNK pathway; PI3K inhibition or dominant-negative AKT downregulates TRAF6/c-Src-induced JNK activation. Co-immunoprecipitation; dominant-negative mutants; PI3K inhibition; kinase activity assays; AP-1 reporter assay European journal of biochemistry Medium 12631284
2023 Rnd3 directly interacts with the RING finger domain of TRAF6, suppressing K63-linked TRAF6 ubiquitination while promoting K48-linked ubiquitination, thereby inhibiting NF-κB activation and promoting TRAF6 degradation; TRAF6 knockdown counters Rnd3 KO-evoked EC pyroptosis in vivo. LC-MS/MS; Co-IP assay; molecular docking; endothelium-specific transgenic mice; ubiquitination assays Clinical and translational medicine Medium 37743632

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 1023 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 368 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 236 20060931
2003 TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 217 14499111
2018 YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. Circulation research 197 29794022
2018 Inhibition of TRAF6 ubiquitin-ligase activity by PRDX1 leads to inhibition of NFKB activation and autophagy activation. Autophagy 186 29929436
2018 Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis. Journal of the American College of Cardiology 165 29406859
2002 TRAF6-deficient mice display hypohidrotic ectodermal dysplasia. Proceedings of the National Academy of Sciences of the United States of America 153 12060722
2011 TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer. Nature communications 151 21629263
2004 The role of TRAF6 in signal transduction and the immune response. Microbes and infection 123 15555541
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 116 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 89 22749815
2018 Assembly mechanism of the CARMA1-BCL10-MALT1-TRAF6 signalosome. Proceedings of the National Academy of Sciences of the United States of America 88 29382759
2013 TRAF6 upregulates expression of HIF-1α and promotes tumor angiogenesis. Cancer research 88 23722539
2008 TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. The Journal of biological chemistry 88 18984593
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
2018 Roles of TRAF6 in Central Nervous System. Current neuropharmacology 71 29651950
2022 USP15 negatively regulates lung cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction. Cell death & disease 70 35422093
2016 Epigallocatechin-3-gallate(EGCG) suppresses melanoma cell growth and metastasis by targeting TRAF6 activity. Oncotarget 70 27791197
2015 TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis. The Journal of clinical investigation 65 26619121
2013 SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria. Molecular biology of the cell 64 23885119
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 63 33840674
2007 Molecular basis for the unique specificity of TRAF6. Advances in experimental medicine and biology 61 17633022
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
2020 The relationship between TRAF6 and tumors. Cancer cell international 55 32905356
2019 TRAF6-p38/JNK-ATF2 axis promotes microglial inflammatory activation. Experimental cell research 52 30763583
2019 GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia. Autophagy 52 30929559
2012 TRAF6 activation in multiple myeloma: a potential therapeutic target. Clinical lymphoma, myeloma & leukemia 52 22440007
2020 Mechanism by which TRAF6 Participates in the Immune Regulation of Autoimmune Diseases and Cancer. BioMed research international 51 33294443
2017 Regulation of MiR-146a and TRAF6 in the Diagnose of Lupus Nephritis. Medical science monitor : international medical journal of experimental and clinical research 51 28549054
2016 TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin. Oncotarget 50 26769849
2019 BANK1 interacts with TRAF6 and MyD88 in innate immune signaling in B cells. Cellular & molecular immunology 49 31243359
2013 TRAF6-mediated ubiquitination of NEMO requires p62/sequestosome-1. Molecular immunology 49 24270048
2012 TRAF6 regulates proliferation, apoptosis, and invasion of osteosarcoma cell. Molecular and cellular biochemistry 49 22886393
2019 Resveratrol induces depletion of TRAF6 and suppresses prostate cancer cell proliferation and migration. The international journal of biochemistry & cell biology 48 31712163
2018 miR-146a promotes cervical cancer cell viability via targeting IRAK1 and TRAF6. Oncology reports 48 29693168
2014 TRAF6 inhibition rescues dexamethasone-induced muscle atrophy. International journal of molecular sciences 48 24955790
2018 Epithelial TRAF6 drives IL-17-mediated psoriatic inflammation. JCI insight 46 30089718
2014 Isolation and characterization of tumor necrosis factor receptor-associated factor 6 (TRAF6) from grouper, Epinephelus tauvina. Fish & shellfish immunology 45 24811008
2022 DNMT1-mediated epigenetic silencing of TRAF6 promotes prostate cancer tumorigenesis and metastasis by enhancing EZH2 stability. Oncogene 43 35804015
2003 TRAF6 and C-SRC induce synergistic AP-1 activation via PI3-kinase-AKT-JNK pathway. European journal of biochemistry 43 12631284
2020 SNHG16/miR-605-3p/TRAF6/NF-κB feedback loop regulates hepatocellular carcinoma metastasis. Journal of cellular and molecular medicine 42 32436333
2019 Ubiquitination of cGAS by TRAF6 regulates anti-DNA viral innate immune responses. Biochemical and biophysical research communications 42 31078259
2018 Mechanism of ubiquitin transfer promoted by TRAF6. Proceedings of the National Academy of Sciences of the United States of America 39 29432170
2021 OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways. Hepatology (Baltimore, Md.) 37 34591986
2017 Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3. The Biochemical journal 37 28507161
2016 Sinomenine down-regulates TLR4/TRAF6 expression and attenuates lipopolysaccharide-induced osteoclastogenesis and osteolysis. European journal of pharmacology 37 26965104
2017 Hepatoprotective effect of quercetin via TRAF6/JNK pathway in acute hepatitis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 36 29174851
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
2007 Roles of TRAF6 in CD40 signaling. Immunologic research 33 17917059
2010 NUMBL interacts with TRAF6 and promotes the degradation of TRAF6. Biochemical and biophysical research communications 31 20079715
2010 Glutaredoxin-1 regulates TRAF6 activation and the IL-1 receptor/TLR4 signalling. Biochemical and biophysical research communications 30 21078302
2024 Enhanced NF-κB activation via HIV-1 Tat-TRAF6 cross-talk. Science advances 29 38241362
2023 Sufu limits sepsis-induced lung inflammation via regulating phase separation of TRAF6. Theranostics 29 37441604
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
2023 Rnd3 suppresses endothelial cell pyroptosis in atherosclerosis through regulation of ubiquitination of TRAF6. Clinical and translational medicine 28 37743632
2021 TRAF6 prevents fatal inflammation by homeostatic suppression of MALT1 protease. Science immunology 28 34767456
2019 TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation. Laboratory investigation; a journal of technical methods and pathology 28 30626891
2019 Sodium butyrate-activated TRAF6-TXNIP pathway affects A549 cells proliferation and migration. Cancer medicine 28 31578830
2020 TRAF6 promotes IL-4-induced M2 macrophage activation by stabilizing STAT6. Molecular immunology 27 33017719
2017 miR‑146b‑5p suppresses glioblastoma cell resistance to temozolomide through targeting TRAF6. Oncology reports 27 29048680
2022 TRAF6 regulates the signaling pathway influencing colorectal cancer function through ubiquitination mechanisms. Cancer science 26 35179811
2016 Cutting Edge: A Cullin-5-TRAF6 Interaction Promotes TRAF6 Polyubiquitination and Lipopolysaccharide Signaling. Journal of immunology (Baltimore, Md. : 1950) 26 27233966
2024 TRAF6 enhances PD-L1 expression through YAP1-TFCP2 signaling in melanoma. Cancer letters 25 38583649
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 24 33201521
2019 TRAF6 mediates human DNA2 polyubiquitination and nuclear localization to maintain nuclear genome integrity. Nucleic acids research 24 31216032
2023 USP7 Inhibits Osteoclastogenesis via Dual Effects of Attenuating TRAF6/TAK1 Axis and Stimulating STING Signaling. Aging and disease 23 37199589
2023 USP25 ameliorates diabetic nephropathy by inhibiting TRAF6-mediated inflammatory responses. International immunopharmacology 23 37657242
2018 TRAF6 regulates EGF-induced cell transformation and cSCC malignant phenotype through CD147/EGFR. Oncogenesis 23 29463844
2018 TRAF6 interacts with and ubiquitinates PIK3CA to enhance PI3K activation. FEBS letters 23 29729098
2017 SMN1 functions as a novel inhibitor for TRAF6-mediated NF-κB signaling. Biochimica et biophysica acta. Molecular cell research 23 28214532
2024 Desulfovibrio vulgaris flagellin exacerbates colorectal cancer through activating LRRC19/TRAF6/TAK1 pathway. Gut microbes 22 39718561
2022 The YTHDF1-TRAF6 pathway regulates the neuroinflammatory response and contributes to morphine tolerance and hyperalgesia in the periaqueductal gray. Journal of neuroinflammation 22 36550542
2020 Destablilization of TRAF6 by DRAK1 Suppresses Tumor Growth and Metastasis in Cervical Cancer Cells. Cancer research 22 32265222
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
2023 CD4+ T-Cell Legumain Deficiency Attenuates Hypertensive Damage via Preservation of TRAF6. Circulation research 21 38047378
2021 TRAF6 Contributes to CFA-Induced Spinal Microglial Activation and Chronic Inflammatory Pain in Mice. Cellular and molecular neurobiology 21 33694132
2018 TRAF6 mediates high glucose-induced endothelial dysfunction. Experimental cell research 21 30017935
2022 miR-146a contributes to atherosclerotic plaque stability by regulating the expression of TRAF6 and IRAK-1. Molecular biology reports 20 35195809
2014 TRAF6 is a novel regulator of Notch signaling in Drosophila melanogaster. Cellular signalling 20 25280943
2018 RSK2 is required for TRAF6 phosphorylation-mediated colon inflammation. Oncogene 19 29563609
2005 TRAF6 and Src kinase activity regulates Cot activation by IL-1. Cellular signalling 19 16371247
2020 TRAF6 Promotes Gastric Cancer Cell Self-Renewal, Proliferation, and Migration. Stem cells international 18 32724313
2016 High TRAF6 Expression Is Associated With Esophageal Carcinoma Recurrence and Prompts Cancer Cell Invasion. Oncology research 18 27697099
2024 BUB1 potentiates gastric cancer proliferation and metastasis by activating TRAF6/NF-κB/FGF18 through m6A modification. Life sciences 17 39025206
2021 microRNA-125a targets MAVS and TRAF6 to modulate interferon signaling and promote HCV infection. Virus research 17 33577860
2021 The Antiviral Enzyme, Viperin, Activates Protein Ubiquitination by the E3 Ubiquitin Ligase, TRAF6. Journal of the American Chemical Society 17 33779167
2019 TRAF6 maintains mammary stem cells and promotes pregnancy-induced mammary epithelial cell expansion. Communications biology 17 31396572
2017 Combined TRAF6 Targeting and Proteasome Blockade Has Anti-myeloma and Anti-Bone Resorptive Effects. Molecular cancer research : MCR 17 28122920
2010 TRAF6 negatively regulates the Jak1-Erk pathway in interleukin-2 signaling. Genes to cells : devoted to molecular & cellular mechanisms 17 21155952

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