Affinage

TRAF3

TNF receptor-associated factor 3 · UniProt Q13114

Length
568 aa
Mass
64.5 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: UniProt preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAF3 is a multifunctional intracellular adaptor and ubiquitin-pathway hub that couples TNF-receptor-superfamily and innate immune receptors to opposing transcriptional outputs, first identified as a direct CD40 cytoplasmic-tail binding partner whose TRAF-C domain mediates receptor binding and homodimerization (PMID:7533327). Structurally, a single adaptive hydrophobic crevice in the TRAF domain accommodates diverse partners including CD40, LTβR, BAFF-R, TANK and viral LMP1, explaining how one surface integrates many receptor inputs (PMID:17633021). In innate antiviral signaling, TRAF3 is a positive regulator of type I interferon induction, bridging TLR adaptors (MyD88, TRIF, IRAK1) and the RLR adaptor MAVS/Cardif to the IRF3/7 kinases TBK1 and IKK-ε; TRAF-domain point mutations that abolish MAVS binding also abolish IFN production (PMID:16306937, PMID:16306936, PMID:16858409). This bridging function depends on activating K63-linked ubiquitination of TRAF3 catalyzed by HECTD3 (at K138), TRIM24 (at K429/K436), and Nedd4l (cysteine ubiquitination at Cys56/Cys124 that licenses further K48/K63 modification and TBK1 binding), each enabling TRAF3-TBK1 complex assembly on mitochondria (PMID:29920190, PMID:32324863, PMID:33608556). In a counterbalancing role, TRAF3 is a critical negative regulator of non-canonical NF-κB signaling: it maintains NIK in a degradation-competent complex with TRAF2 and cIAP1/2, and receptor engagement triggers cIAP-mediated K48-ubiquitination and proteasomal destruction of TRAF3 — a step requiring the RING domain of TRAF2 — which releases and stabilizes NIK to drive p100 processing (PMID:17015635, PMID:18997792, PMID:20348096, PMID:20185819). TRAF3 abundance is tuned by deubiquitinases that stabilize it (OTUB1/2, OTUD7B, USP11) and by stabilizing or destabilizing factors (iOPN, Parkin, Triad3A) (PMID:19996094, PMID:27026194, PMID:29903906, PMID:33198776). Beyond these core axes, TRAF3 acts as a resident nuclear protein in B cells, where its TRAF-C-domain NLS targets it to associate with and destabilize CREB, repressing CREB-driven transcription including Mcl-1 (PMID:26755589), and it ubiquitinates substrates including TAK1, STAT6, ULK1, ECH1 and MFF to control hepatic metabolism, macrophage polarization, inflammasome-driven cell death, ferroptosis, and mitochondrial apoptosis (PMID:26882989, PMID:37474750, PMID:32275117, PMID:39932808, PMID:34745083).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Established TRAF3 as a direct receptor adaptor by identifying it as a CD40 cytoplasmic-tail binding protein and mapping the binding determinant.

    Evidence Yeast two-hybrid screen plus domain-deletion mapping defining the TRAF-C domain

    PMID:7533327

    Open questions at the time
    • Did not define downstream signaling consequences of the interaction
    • No structural detail of the binding interface
  2. 2005 High

    Defined TRAF3 as a non-redundant positive node for type I IFN and IL-10 induction, linking TLR adaptors to the IRF kinases.

    Evidence Adaptor-complex isolation and TRAF3-deficient myeloid cells/fibroblasts with cytokine and virus-infection readouts

    PMID:16306936 PMID:16306937

    Open questions at the time
    • Mechanism of TBK1 recruitment by TRAF3 not resolved at molecular level
    • Did not address how TRAF3 distinguishes IFN from pro-inflammatory output
  3. 2006 High

    Extended the antiviral role to RLR signaling by demonstrating a direct TRAF-domain–MAVS/Cardif interaction required for IFN production.

    Evidence In vitro binding plus TRAF-domain mutagenesis with IFN induction readout

    PMID:16858409

    Open questions at the time
    • Did not establish ubiquitin requirement for the MAVS-coupled function
    • Recruitment to mitochondria not addressed
  4. 2006 High

    Genetically established TRAF3 as the critical brake on non-canonical NF-κB by showing NIK accumulation upon TRAF3 loss and rescue of lethality by p100 deletion.

    Evidence TRAF3-/-;p100-/- double-knockout epistasis, NIK Western blotting, B cell phenotyping

    PMID:17015635

    Open questions at the time
    • Did not define the biochemical mechanism of NIK turnover
    • Roles of TRAF2/cIAP not yet incorporated
  5. 2008 High

    Resolved the NIK-control mechanism: TRAF3 is degraded by a TRAF2-cIAP1/2 complex upon receptor engagement, releasing NIK.

    Evidence Ubiquitination assays, cIAP1/2 and TRAF2 knockouts, receptor stimulation, proteasome inhibition

    PMID:18997792

    Open questions at the time
    • Did not resolve which RING domain catalyzes the modification
    • Receptor-specific kinetics not fully mapped
  6. 2010 High

    Clarified receptor competition and ligase assignment: LTβR and NIK share a TRAF3 recognition crevice, and stimulus-dependent TRAF3 degradation requires the TRAF2 RING, not TRAF3's own.

    Evidence Charge-repulsion crevice mutagenesis, Co-IP, ubiquitination and proteasome-inhibitor studies; siRNA depletion for dual canonical/non-canonical regulation

    PMID:20185819 PMID:20348096

    Open questions at the time
    • Medium-confidence dual-pathway claim rests on single-lab siRNA work
    • Quantitative competition kinetics between NIK and receptor not defined
  7. 2007 High

    Provided the structural basis for TRAF3's promiscuous receptor binding via a single adaptive crevice.

    Evidence X-ray crystallography of five TRAF3 TRAF-domain complexes (CD40, LTβR, BAFF-R, TANK, LMP1)

    PMID:17633021

    Open questions at the time
    • Structures do not capture the ubiquitin-ligase or NIK-degradation complex
    • Conformational changes during signaling not visualized
  8. 2016 High

    Identified a nuclear function: TRAF3's TRAF-C NLS directs it to destabilize CREB and repress pro-survival transcription in B cells.

    Evidence Fractionation, Co-IP, TRAF-C mutagenesis, ubiquitination and reporter assays in B cell–specific knockouts

    PMID:26755589

    Open questions at the time
    • Mechanism by which TRAF3 reduces CREB ubiquitination/stability not fully defined
    • Nuclear vs cytoplasmic partitioning signals not mapped
  9. 2016 High

    Connected TRAF3 to hepatic metabolic disease by defining a TRAF3-TAK1 ubiquitination axis driving steatosis.

    Evidence Liver-specific knockout and transgenic mice, Co-IP, ubiquitination assay, TAK1-inhibitor rescue, high-fat-diet model

    PMID:26882989

    Open questions at the time
    • Linkage type of TAK1 ubiquitination not specified
    • Tissue-selectivity of this axis vs immune cells unclear
  10. 2018 High

    Defined site-specific activating ubiquitination (HECTD3 at K138; TRIM24 at K429/K436) as the trigger for TRAF3-TBK1 complex formation in antibacterial/antiviral IFN responses.

    Evidence Hectd3- and Trim24-knockout mice, site-directed ubiquitination mutagenesis, Co-IP, infection models

    PMID:29920190 PMID:32324863

    Open questions at the time
    • Hierarchy and interplay among multiple K63-ligases unresolved
    • Whether modifications are auto- or trans-catalyzed in vivo not fully settled
  11. 2021 High

    Revealed a priming layer of regulation in which Nedd4l-mediated K29-cysteine ubiquitination of TRAF3 zinc fingers licenses subsequent K48/K63 modification and TBK1 binding.

    Evidence Nedd4l-knockout mice, Cys56/Cys124 mutagenesis, K29-linkage ubiquitination assay, Co-IP, infection

    PMID:33608556

    Open questions at the time
    • Order of cysteine vs lysine ubiquitination in vivo not resolved
    • Reader for K29 chains not identified
  12. 2019 High

    Identified mitochondrial bridging and STING crosstalk: TRAF3IP3 recruits TRAF3 to MAVS, and TRAF3 couples MAVS to STING-dependent TBK1 activation, while NIK release diverts DNA-sensing output.

    Evidence Traf3ip3-knockout mice, Co-IP, mitochondrial localization; TRAF3/NIK-deficient cells with STING and NIK oligomerization assays; EV-A71 rescue experiments

    PMID:30018345 PMID:31390091 PMID:36823147

    Open questions at the time
    • Opposite RNA vs DNA pathway roles (Medium) from single lab
    • Spatial coordination of MAVS- and STING-coupled pools unclear
  13. 2023 Medium

    Expanded the substrate repertoire to non-immune-receptor targets controlling cell fate and metabolism (STAT6, ULK1, ECH1, MFF).

    Evidence Site-specific ubiquitination mutagenesis, ubiquitomics, mitochondrial import assays, conditional knockouts and tumor/apoptosis models

    PMID:32275117 PMID:34745083 PMID:37474750 PMID:39932808

    Open questions at the time
    • Each substrate validated by a single lab
    • Whether these activities require the canonical TRAF2/cIAP complex not uniformly tested
  14. 2021 Medium

    Mapped the deubiquitinase counter-regulation that sets TRAF3 abundance and downstream pathway tone (OTUB1/2, OTUD7B, USP11; stabilizers iOPN; destabilizers Parkin/Triad3A).

    Evidence Co-IP, ubiquitination assays, catalytic-mutant and knockdown/knockout studies in viral, cancer, and ischemia models

    PMID:19996094 PMID:27026194 PMID:29903906 PMID:33198776 PMID:37000116

    Open questions at the time
    • USP11 cardiomyocyte axis is Low-confidence single study
    • Linkage specificity removed by each DUB not uniformly defined
  15. 2009 High

    Demonstrated physiological B-cell requirement for TRAF2/TRAF3 in CD40-driven class switch recombination and germinal center formation.

    Evidence CD40 binding-site mutant transgenes in CD40-knockout mice with CSR and NF-κB readouts

    PMID:19228877

    Open questions at the time
    • Does not separate adaptor vs ligase contributions of TRAF3
    • Mechanistic coupling to CSR machinery unaddressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRAF3 dynamically partitions among its opposing roles — antiviral IFN amplifier, non-canonical NF-κB brake, nuclear CREB repressor, and mitochondrial death/metabolism regulator — within a single cell remains unresolved.
  • No unified model of how ubiquitin-linkage choice routes TRAF3 to distinct fates
  • Spatial/temporal switch between cytosolic, mitochondrial, and nuclear pools uncharacterized
  • Hierarchy among the many competing E3 ligases and DUBs in vivo not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016874 ligase activity 4 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 7 R-HSA-392499 Metabolism of proteins 6 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 1
Partners
CD40MAVSMFFNIKSTAT6TAK1TBK1TRAF2
Complex memberships
MAVS-TRAF3IP3-TRAF3 mitochondrial complexTRAF3-TBK1 antiviral signaling complexTRAF3-TRAF2-cIAP1/2-NIK degradation complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 TRAF3 (then called CRAF1) was identified as a direct binding partner of the CD40 cytoplasmic tail; the TRAF-C domain of TRAF3 was necessary and sufficient for CD40 binding and homodimerization. Yeast two-hybrid screen; domain deletion analysis Science High 7533327
2005 TRAF3 is recruited to TLR adaptor MyD88-containing signaling complexes and is essential for induction of type I interferons and IL-10 but dispensable for pro-inflammatory cytokines; TRAF3 is required to recruit TBK1 into TIR signaling complexes. Biochemical isolation of dimerized-adaptor signaling complexes; TRAF3-deficient myeloid cells from knockout mice; cytokine measurements Nature High 16306937
2005 TRAF3 associates with TLR adaptors TRIF and IRAK1, as well as downstream IRF3/7 kinases TBK1 and IKK-ε, placing TRAF3 as a critical link between TLR adaptors and kinases required for IRF activation and type I IFN production; TRAF3-deficient fibroblasts are also defective in TLR-independent type I IFN responses to direct virus infection. Co-immunoprecipitation; TRAF3-deficient cells; virus infection assays Nature High 16306936
2006 TRAF3 directly interacts with the MAVS/Cardif adaptor through a TRAF-interaction motif (TIM) in Cardif and the TRAF domain of TRAF3; mutation of two critical amino acids in the TRAF domain abolishes both Cardif binding and TRAF3-dependent IFN production after viral infection. In vitro binding assays; site-directed mutagenesis of TRAF domain; IFN induction assays The EMBO Journal High 16858409
2006 Loss of TRAF3 results in constitutive non-canonical NF-κB activity and profound accumulation of NF-κB-inducing kinase (NIK) in TRAF3-deficient cells; the early postnatal lethality of TRAF3-knockout mice is rescued by compound loss of the non-canonical NF-κB p100 gene, genetically establishing TRAF3 as a critical negative modulator of the non-canonical NF-κB pathway. Genetic epistasis (TRAF3-/-;p100-/- double-knockout rescue); Western blotting for NIK; B cell phenotyping The Journal of Experimental Medicine High 17015635
2008 TRAF3 is constitutively degraded in a TRAF2- and cIAP1/2-dependent manner; receptor (CD40 or BAFF-R) activation causes cIAP1/2-mediated K48-linked ubiquitination and proteasomal degradation of TRAF3, which releases NIK from the cIAP1-cIAP2-TRAF2 ubiquitin ligase complex, leading to NIK stabilization and NF-κB2-p100 processing. Ubiquitination assays; cIAP1/2 and TRAF2 knockouts; receptor stimulation experiments; proteasome inhibitor studies Nature Immunology High 18997792
2009 Deubiquitinating enzymes OTUB1 and OTUB2 interact with TRAF3, remove ubiquitin from TRAF3, and negatively regulate virus-triggered type I IFN induction; overexpression inhibits IRF3 and NF-κB activation while knockdown has the opposite effect. Co-immunoprecipitation; ubiquitination assay; overexpression/knockdown; virus infection The Journal of Biological Chemistry Medium 19996094
2010 A charge-repulsion mutation in the receptor-binding crevice of TRAF3 ablated binding of both LTβR and NIK, suggesting they share a common recognition site; ligand-activated LTβR competitively displaces NIK from TRAF3, and recruited TRAF3/TRAF2 redirects ubiquitin ligase activity to polyubiquitinate TRAF3 and TRAF2 for proteasomal degradation; stimulus-dependent TRAF3 degradation required the RING domain of TRAF2 (not TRAF3). Site-directed mutagenesis; co-immunoprecipitation; ubiquitination assay; proteasome inhibitor studies The Journal of Biological Chemistry High 20348096
2010 TRAF3 negatively regulates both canonical and non-canonical NF-κB signaling by LTβR via two distinct mechanisms: by competitively blocking TRAF2 recruitment to the activated receptor (thereby inhibiting canonical IκBα phosphorylation) and by autonomously suppressing non-canonical NF-κB components (NIK, p100, RelB) independent of receptor stimulation. siRNA-mediated TRAF3 depletion; Western blotting; receptor-specific signaling assays; co-immunoprecipitation The Journal of Biological Chemistry Medium 20185819
2014 NEDD4 E3 ubiquitin ligase constitutively interacts with CD40 and mediates K63-linked ubiquitination of TRAF3; this ubiquitination of TRAF3 by NEDD4 is critical for CD40-mediated AKT activation. Co-immunoprecipitation; K63-linked ubiquitination assay; AKT phosphorylation readout; genetic knockdown Nature Communications Medium 25072696
2016 Intracellular osteopontin (iOPN) interacts with TRAF3 via its C-terminal fragment and inhibits Triad3A-mediated K48-linked polyubiquitination and degradation of TRAF3, thereby stabilizing TRAF3 and promoting antiviral type I IFN production. Co-immunoprecipitation; ubiquitination assay; OPN-deficient mice; virus infection assay Scientific Reports Medium 27026194
2016 TRAF3 inhibits IL-6 receptor signaling in B cells by facilitating the association of phosphatase PTPN22 with JAK1, which blocks STAT3 phosphorylation, thereby limiting plasma cell differentiation. B cell-specific TRAF3-knockout mice; co-immunoprecipitation; phosphorylation assays; genetic rescue with IL-6 deletion Science Signaling High 26329582
2016 TRAF3 is a resident nuclear protein in B cells; the TRAF-C domain contains a functional nuclear localization signal; nuclear TRAF3 associates with transcriptional regulator CREB, reduces CREB stability (via decreased CREB ubiquitination), and inhibits CREB-mediated transcription including expression of the pro-survival protein Mcl-1. Cell fractionation; co-immunoprecipitation; TRAF-C domain deletion/mutagenesis; ubiquitination assay; luciferase reporter assay; B cell-specific TRAF3-knockout mice Proceedings of the National Academy of Sciences High 26755589
2018 E3 ligase HECTD3 mediates K63-linked polyubiquitination of TRAF3 specifically at residue K138; this modification enables TRAF3-TBK1 complex formation and is required for type I IFN induction during intracellular bacterial infection. Both DOC and HECT domains of HECTD3 interact with TRAF3. Hectd3-knockout mice; ubiquitination assay with site-directed mutagenesis (K138); Co-immunoprecipitation; in vivo bacterial infection The Journal of Clinical Investigation High 29920190
2018 TRAF3 forms a complex with TRAF2 and cIAP1 and mediates K48-linked ubiquitination and proteasomal degradation of ULK1; loss of ULK1 promotes inflammasome activation and pyroptosis in macrophages, linking TRAF3 to regulation of mitochondrial ROS and inflammatory cell death. Co-immunoprecipitation; ubiquitination assay; siRNA knockdown; inflammasome/caspase-1 activation assay FASEB Journal Medium 32275117
2018 TRAF3 promotes TCR signaling by associating with the TCR inhibitor Csk and promoting Csk dissociation from the plasma membrane, and by regulating localization of PTPN22; loss of TRAF3 increases membrane-associated Csk and PTPN22, decreasing activating phosphorylation of Lck. T cell-specific TRAF3-knockout mice; membrane fractionation; co-immunoprecipitation; Lck phosphorylation assay Scientific Reports Medium 28522807
2018 Parkin E3 ubiquitin ligase interacts with TRAF3 and promotes Lys48-linked ubiquitination of TRAF3, targeting it for proteasomal degradation and thereby negatively regulating antiviral innate immune signaling. Co-immunoprecipitation; K48-linked ubiquitination assay; Parkin overexpression and knockout; virus infection assay The Journal of Biological Chemistry Medium 29903906
2018 In the TRAF3-NIK module, TRAF3 positively regulates RNA pathway IFN induction but negatively regulates DNA pathway IFN induction; loss of TRAF3 stabilizes NIK, which then activates STING-dependent DNA sensing independently of alternative NF-κB components, requiring NIK autophosphorylation and oligomerization. TRAF3- and NIK-deficient cells; virus infection; STING signaling assays; NIK autophosphorylation/oligomerization analysis Nature Communications Medium 30018345
2019 TRAF3IP3 accumulates on mitochondria upon virus infection and bridges MAVS and TRAF3, facilitating recruitment of TRAF3 to MAVS for TBK1-IRF3 activation; Traf3ip3-deficient mice show severely compromised IFN production and vulnerability to RNA virus infection. Traf3ip3-knockout mice; co-immunoprecipitation; mitochondrial localization; virus infection The EMBO Journal High 31390091
2019 TGFβ1 induces degradation of TRAF3 in mesenchymal progenitor cells via GSK-3β, reducing TRAF3 protein levels during aging; TRAF3 normally prevents β-catenin degradation in mesenchymal progenitors; deletion of TRAF3 in mesenchymal progenitors activates NF-κB RelA and RelB to promote RANKL expression, enhancing osteoclastogenesis. Conditional TRAF3-knockout mice in mesenchymal progenitors; GSK-3β inhibitor studies; β-catenin and ubiquitination assays; bone phenotyping Nature Communications Medium 31243287
2020 TRIM24 directly mediates K63-linked ubiquitination of TRAF3 at K429/K436 on mitochondria upon VSV infection; this modification enables TRAF3 association with MAVS and TBK1, activating downstream antiviral signaling; ablation of TRIM24 impairs IFN-I induction and sensitizes mice to VSV. TRIM24-knockout mice; ubiquitination assay with site-directed mutagenesis; Co-immunoprecipitation; mitochondrial fractionation; virus infection The Journal of Experimental Medicine High 32324863
2020 OTUD7B deubiquitinase directly binds TRAF3 (but not NIK) via its OTU domain and deubiquitinates TRAF3, inhibiting TRAF3 proteolysis, thereby preventing NIK accumulation and non-canonical NF-κB pathway activation; catalytic mutant OTUD7B (C194S/H358R) abolishes this activity. Co-immunoprecipitation; ubiquitination assay; OTU-domain catalytic mutant; shRNA knockdown/overexpression; in vivo lung cancer metastasis model Journal of Experimental & Clinical Cancer Research Medium 33198776
2021 E3 ligase Nedd4l catalyzes K29-linked ubiquitination of TRAF3 specifically at Cys56 and Cys124 (zinc-finger cysteines); this cysteine ubiquitination enhances association of TRAF3 with cIAP1/2 and HECTD3 and increases K48/K63-linked ubiquitination of TRAF3; Nedd4l deficiency impairs TRAF3-TBK1 binding, TBK1/IRF3 phosphorylation, and antiviral IFN production in vivo. Nedd4l-knockout mice; site-directed mutagenesis of Cys56/Cys124; K29-linked ubiquitination assay; Co-immunoprecipitation; virus infection Nature Communications High 33608556
2021 EV-D68 protease 2Apro cleaves TRAF3 at the C-terminal region; a catalytic cysteine-to-alanine mutation (C107A) in 2Apro abolishes TRAF3 cleavage, and mutation of TRAF3-G462A confers resistance to 2Apro cleavage; this cleavage suppresses IRF3 activation and IFN-β production. Protease cleavage assay; site-directed mutagenesis; IRF3 activation assay; IFN-β reporter Journal of Virology Medium 33148796
2021 USP11 deubiquitinase interacts with TRAF3 and stabilizes it by removing ubiquitin; increased TRAF3 stability promotes IKKβ/NF-κB pathway activation and pyroptosis in cardiomyocytes under ischemia-reperfusion injury. Co-immunoprecipitation; ubiquitination assay; siRNA knockdown; ischemia-reperfusion model Balkan Medical Journal Low 37000116
2016 Hepatocyte TRAF3 directly binds TAK1 and induces TAK1 ubiquitination and subsequent autophosphorylation, enhancing activation of IKKβ-NF-κB and MKK-JNK-IRS1(Ser307) signaling cascades while disrupting AKT-GSK3β/FOXO1 signaling; the TRAF3-TAK1 interaction and TAK1 ubiquitination are required for TRAF3-driven hepatic steatosis. Liver-specific TRAF3-knockout and transgenic overexpression mice; Co-immunoprecipitation; ubiquitination assay; TAK1 inhibitor rescue; high-fat diet model Nature Communications High 26882989
2019 TRAF3 interacts with MAVS and promotes STING-mediated TBK1 phosphorylation; TRAF3 is required for cGAS-STING activation in enterovirus A71 infection; EV-A71 protease 2Apro targets TRAF3 to suppress cGAS-STING signaling, and supplementation with TRAF3 rescues 2Apro-mediated suppression. Co-immunoprecipitation; overexpression/knockdown; TBK1 phosphorylation assay; rescue experiments with TRAF3 supplementation Signal Transduction and Targeted Therapy Medium 36823147
2017 NDR1 kinase interacts with TRAF3 and prevents TRAF3 binding to IL-17R, thereby promoting formation of the IL-17R-Act1-TRAF6 complex and downstream NF-κB/MAPK signaling; this competitive binding is independent of NDR1 kinase activity. Co-immunoprecipitation; competitive binding assay; NDR1-deficient mice; kinase-dead mutant; IL-17 signaling readouts EMBO Reports Medium 28219902
2023 TRAF3 promotes STAT6 K450 ubiquitination and transcriptional activity in macrophages; TRAF3 deficiency specifically reduces ubiquitination at STAT6 K450 and K129, abolishes IL-4-induced M2 macrophage polarization, and suppresses tumor growth in a melanoma mouse model. Quantitative ubiquitomics; ubiquitination assay; site-mutation analysis (K450, K129); luciferase reporter; myeloid TRAF3-knockout mice Cell Death and Differentiation Medium 37474750
2021 TRAF3 interacts with MFF (Mitochondrial Fission Factor) in B lymphocytes; in resting B cells deprived of survival factors, TRAF3 is mobilized to mitochondria through MFF interaction, where it triggers mitochondria-dependent apoptosis; TRAF3 co-expression with MFF decreases phosphorylation and ubiquitination of MFF. Co-immunoprecipitation; GST pull-down; mitochondrial fractionation/localization; TRAF3-deficient B cells; mitochondrial function assays Frontiers in Immunology Medium 34745083
2025 TRAF3 interacts with ECH1 (enoyl-CoA hydratase 1) and mediates K63-linked ubiquitination of ECH1 at Lys214; this ubiquitination impedes TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promotes oxidation of polyunsaturated fatty acids and limits lipid peroxidation; TRAF3 loss in GBM thus enhances FAO and protects against ferroptosis. Co-immunoprecipitation; K63-linked ubiquitination assay; site-directed mutagenesis (K214); mitochondrial import assay; TRAF3-overexpression in GBM mouse models; ferroptosis assay The Journal of Clinical Investigation Medium 39932808
2007 Crystal structures of the TRAF3 TRAF domain in complex with binding partners (CD40, LTβR, BAFF-R, TANK, and EBV LMP1) reveal that all recognition motifs are accommodated within a single hydrophobic crevice on TRAF3, and that this binding interface is structurally adaptive. X-ray crystallography of five distinct TRAF3 complexes Advances in Experimental Medicine and Biology High 17633021
2006 CD40 mediates apoptosis in carcinoma cells through rapid post-translational upregulation of TRAF3 protein (without change in mRNA), followed by JNK/AP-1 pathway activation and caspase-9/caspase-3-dependent intrinsic apoptosis; TRAF3 knockdown abrogates JNK/AP-1 activation and CD40-mediated apoptosis. TRAF3 siRNA knockdown; JNK/AP-1 activation assays; caspase activity assays; CD40 re-expression in CD40-negative cells Cell Death and Differentiation Medium 16429118
2009 TRAF2 and TRAF3 each independently mediate immunoglobulin class switch recombination driven by CD40; mice expressing CD40 that selectively lacks binding to both TRAF2 and TRAF3 lose virtually all CD40-driven CSR, germinal center formation, and non-canonical NF-κB activation. Genetic epistasis using CD40 binding-site mutant transgenes in CD40-knockout mice; CSR assays; NF-κB activation measurement International Immunology High 19228877
2015 TRAF3 limits RANKL-induced osteoclast formation by promoting proteasomal degradation of NIK in a complex with TRAF2 and cIAP proteins in osteoclast precursors; chloroquine prevents TRAF3 degradation in osteoclast precursors and inhibits osteoclast formation in vitro and bone destruction in vivo. Conditional TRAF3-knockout mice; NIK stability assays; chloroquine treatment in vitro and in vivo (ovariectomy/PTH models) Frontiers in Immunology (review with primary data citations) Medium 30323820

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 755 16306937
2005 Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 701 16306936
2008 Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nature immunology 524 18997792
1995 Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science (New York, N.Y.) 439 7533327
2011 Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nature reviews. Immunology 395 21660053
2006 Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. The EMBO journal 349 16858409
2001 Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. The EMBO journal 257 11296228
1990 Mutational activation of c-raf-1 and definition of the minimal transforming sequence. Molecular and cellular biology 241 2188091
2021 Cap 1 Messenger RNA Synthesis with Co-transcriptional CleanCap® Analog by In Vitro Transcription. Current protocols 175 33524237
2000 The discovery of potent cRaf1 kinase inhibitors. Bioorganic & medicinal chemistry letters 172 10698440
2009 Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6. The Journal of biological chemistry 161 19996094
2004 Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. The Journal of clinical investigation 161 15467832
1997 Characterization of LMP-1's association with TRAF1, TRAF2, and TRAF3. Journal of virology 146 9151858
2006 Rescue of TRAF3-null mice by p100 NF-kappa B deficiency. The Journal of experimental medicine 143 17015635
2016 Hepatocyte TRAF3 promotes liver steatosis and systemic insulin resistance through targeting TAK1-dependent signalling. Nature communications 114 26882989
2021 Expression of miRNA-29 in Pancreatic β Cells Promotes Inflammation and Diabetes via TRAF3. Cell reports 109 33406428
2021 E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Nature communications 97 33608556
2011 Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions. Immunological reviews 90 22017431
2015 Targeting TRAF3 signaling protects against hepatic ischemia/reperfusions injury. Journal of hepatology 88 26334576
2019 TGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis. Nature communications 79 31243287
1994 Enzymatic characteristics of the c-Raf-1 protein kinase. Proceedings of the National Academy of Sciences of the United States of America 77 8108400
2014 Genetic inactivation of TRAF3 in canine and human B-cell lymphoma. Blood 73 25468570
2012 Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. British journal of haematology 73 22469134
2010 TRAF3 controls activation of the canonical and alternative NFkappaB by the lymphotoxin beta receptor. The Journal of biological chemistry 71 20185819
2023 TRAF3/STAT6 axis regulates macrophage polarization and tumor progression. Cell death and differentiation 70 37474750
2013 TRAF3 regulates the effector function of regulatory T cells and humoral immune responses. The Journal of experimental medicine 69 24378539
2020 Downregulation of circular RNA HECTD1 induces neuroprotection against ischemic stroke through the microRNA-133b/TRAF3 pathway. Life sciences 66 33148417
2010 Allosteric regulation of the ubiquitin:NIK and ubiquitin:TRAF3 E3 ligases by the lymphotoxin-beta receptor. The Journal of biological chemistry 65 20348096
2006 The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling. EMBO reports 65 16311516
2014 Myeloid cell TRAF3 regulates immune responses and inhibits inflammation and tumor development in mice. Journal of immunology (Baltimore, Md. : 1950) 64 25422508
2020 Lentinan-functionalized Selenium Nanoparticles target Tumor Cell Mitochondria via TLR4/TRAF3/MFN1 pathway. Theranostics 63 32802180
2006 A novel mechanism of CD40-induced apoptosis of carcinoma cells involving TRAF3 and JNK/AP-1 activation. Cell death and differentiation 63 16429118
2018 Bone Remodeling and the Role of TRAF3 in Osteoclastic Bone Resorption. Frontiers in immunology 62 30323820
2007 TRAF3 and its biological function. Advances in experimental medicine and biology 57 17633016
2018 TRAF3 as a Multifaceted Regulator of B Lymphocyte Survival and Activation. Frontiers in immunology 55 30319624
2018 HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection. The Journal of clinical investigation 53 29920190
2020 TRIM24 facilitates antiviral immunity through mediating K63-linked TRAF3 ubiquitination. The Journal of experimental medicine 51 32324863
1993 Oncogene activation: c-raf-1 gene mutations in experimental and naturally occurring tumors. Toxicology letters 51 8451761
2020 Novel Pathway for Chloramphenicol Catabolism in the Activated Sludge Bacterial Isolate Sphingobium sp. CAP-1. Environmental science & technology 50 32412239
2019 TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiviral innate immunity. The EMBO journal 46 31390091
2014 NEDD4 ubiquitinates TRAF3 to promote CD40-mediated AKT activation. Nature communications 46 25072696
2016 TRAF3 deficiency promotes metabolic reprogramming in B cells. Scientific reports 45 27752131
2022 Mesenchymal Stem Cell-Derived Exosome-Loaded microRNA-129-5p Inhibits TRAF3 Expression to Alleviate Apoptosis and Oxidative Stress in Heart Failure. Cardiovascular toxicology 43 35546649
2017 NDR1 protein kinase promotes IL-17- and TNF-α-mediated inflammation by competitively binding TRAF3. EMBO reports 43 28219902
2016 Nuclear TRAF3 is a negative regulator of CREB in B cells. Proceedings of the National Academy of Sciences of the United States of America 42 26755589
2015 The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development. Science signaling 42 26329582
1999 Tangled webs: evidence of cross-talk between c-Raf-1 and Akt. Science's STKE : signal transduction knowledge environment 40 11865188
2023 The Roles of TRAF3 in Immune Responses. Disease markers 39 36845015
2020 TRAF3 promotes ROS production and pyroptosis by targeting ULK1 ubiquitination in macrophages. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 32275117
2024 Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα-TRAF3-TAK1-MAPK axis. Signal transduction and targeted therapy 37 39406701
2020 OTUD7B suppresses Smac mimetic-induced lung cancer cell invasion and migration via deubiquitinating TRAF3. Journal of experimental & clinical cancer research : CR 37 33198776
2016 Intracellular osteopontin stabilizes TRAF3 to positively regulate innate antiviral response. Scientific reports 37 27026194
2018 A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling. Nature communications 36 30018345
2015 Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity. American journal of physiology. Endocrinology and metabolism 35 25628422
2013 Roles for TNF-receptor associated factor 3 (TRAF3) in lymphocyte functions. Cytokine & growth factor reviews 35 24433987
2000 Both amino- and carboxyl-terminal domains of TRAF3 negatively regulate NF-kappaB activation induced by OX40 signaling. Biochemical and biophysical research communications 35 10860842
2015 TRAF3, ubiquitination, and B-lymphocyte regulation. Immunological reviews 34 26085206
2023 FXYD3 enhances IL-17A signaling to promote psoriasis by competitively binding TRAF3 in keratinocytes. Cellular & molecular immunology 33 36693922
2007 Multiple roles of TRAF3 signaling in lymphocyte function. Immunologic research 33 17917053
2022 Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations. Science immunology 32 35960817
2016 TRAF3 as a powerful and multitalented regulator of lymphocyte functions. Journal of leukocyte biology 31 27154354
2021 Hypothermic oxygenated perfusion inhibits HECTD3-mediated TRAF3 polyubiquitination to alleviate DCD liver ischemia-reperfusion injury. Cell death & disease 30 33627626
2020 MiR-1307-5p targeting TRAF3 upregulates the MAPK/NF-κB pathway and promotes lung adenocarcinoma proliferation. Cancer cell international 30 33061854
2020 Methionine selenium antagonizes LPS-induced necroptosis in the chicken liver via the miR-155/TRAF3/MAPK axis. Journal of cellular physiology 30 33151563
2017 TRAF3 enhances TCR signaling by regulating the inhibitors Csk and PTPN22. Scientific reports 30 28522807
2016 TRAF3 signaling: Competitive binding and evolvability of adaptive viral molecular mimicry. Biochimica et biophysica acta 30 27208423
2015 TRAF3: a novel tumor suppressor gene in macrophages. Macrophage 29 26661944
2023 TRAF3 activates STING-mediated suppression of EV-A71 and target of viral evasion. Signal transduction and targeted therapy 28 36823147
2021 Enterovirus D68 Protease 2Apro Targets TRAF3 To Subvert Host Innate Immune Responses. Journal of virology 27 33148796
2019 Various exercise intensities differentially regulate GAP-43 and CAP-1 expression in the rat hippocampus. Gene 26 30682386
2015 Targeting TRAF3 Downstream Signaling Pathways in B cell Neoplasms. Journal of cancer science & therapy 24 25960828
2020 TRAF3 Acts as a Checkpoint of B Cell Receptor Signaling to Control Antibody Class Switch Recombination and Anergy. Journal of immunology (Baltimore, Md. : 1950) 23 32591397
2018 RIP2 promotes glioma cell growth by regulating TRAF3 and activating the NF‑κB and p38 signaling pathways. Oncology reports 23 29693188
2013 Up-regulation and pre-activation of TRAF3 and TRAF5 in inflammatory bowel disease. International journal of medical sciences 22 23329887
2022 TRK-fused gene (TFG) regulates ULK1 stability via TRAF3-mediated ubiquitination and protects macrophages from LPS-induced pyroptosis. Cell death & disease 21 35091545
2019 Cell type-specific function of TRAF2 and TRAF3 in regulating type I IFN induction. Cell & bioscience 21 30622699
1999 Activation of c-Raf-1 kinase signal transduction pathway in alpha(7) integrin-deficient mice. The Journal of biological chemistry 21 10488105
1985 Activation of influenza virus-associated RNA polymerase by cap-1 structure (m7GpppNm). Journal of biochemistry 21 4008472
2025 TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism. The Journal of clinical investigation 20 39932808
2023 Ubiquitin-specific protease 11 Aggravates Ischemia-reperfusion-induced Cardiomyocyte Pyroptosis and Injury by Promoting TRAF3 Deubiquitination. Balkan medical journal 20 37000116
2022 Circ_0050908 up-regulates TRAF3 by sponging miR-324-5p to aggravate myocardial ischemia-reperfusion injury. International immunopharmacology 20 35413678
2021 Swine Acute Diarrhea Syndrome Coronavirus Nucleocapsid Protein Antagonizes Interferon-β Production via Blocking the Interaction Between TRAF3 and TBK1. Frontiers in immunology 20 33692778
2019 TRAF3 Is Required for NF-κB Pathway Activation Mediated by HTLV Tax Proteins. Frontiers in microbiology 20 31244811
2015 Roles of TRAF3 in T cells: many surprises. Cell cycle (Georgetown, Tex.) 20 25723057
2020 MiR-92b-3p ameliorates inflammation and autophagy by targeting TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells. International immunopharmacology 19 32822908
2015 Molecular cloning and expression analysis of TRAF3 in chicken. Genetics and molecular research : GMR 19 25966214
2023 Heterogeneous Nuclear Protein U Degraded the m6A Methylated TRAF3 Transcript by YTHDF2 To Promote Porcine Epidemic Diarrhea Virus Replication. Journal of virology 18 36752613
2020 TRAF3IP2 (TRAF3 Interacting Protein 2) Mediates Obesity-Associated Vascular Insulin Resistance and Dysfunction in Male Mice. Hypertension (Dallas, Tex. : 1979) 18 32829657
2018 Parkin negatively regulates the antiviral signaling pathway by targeting TRAF3 for degradation. The Journal of biological chemistry 18 29903906
2014 TRAF3 regulates homeostasis of CD8+ central memory T cells. PloS one 18 25010048
2022 TRAF3/p38-JNK Signalling Crosstalk with Intracellular-TRAIL/Caspase-10-Induced Apoptosis Accelerates ROS-Driven Cancer Cell-Specific Death by CD40. Cells 17 36291141
2021 Mitochondrial Fission Factor Is a Novel Interacting Protein of the Critical B Cell Survival Regulator TRAF3 in B Lymphocytes. Frontiers in immunology 17 34745083
2019 TRAF3 regulates the oncogenic proteins Pim2 and c-Myc to restrain survival in normal and malignant B cells. Scientific reports 17 31501481
2019 Elevated Choline Kinase α-Mediated Choline Metabolism Supports the Prolonged Survival of TRAF3-Deficient B Lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 17 31826940
2019 Dysregulated TRAF3 and BCL2 Expression Promotes Multiple Classes of Mature Non-hodgkin B Cell Lymphoma in Mice. Frontiers in immunology 16 30687320
2018 Dihydromyricetin inhibits caerulin-induced TRAF3-p38 signaling activation and acute pancreatitis response. Biochemical and biophysical research communications 16 30055802
2007 Protein-protein interactions in TRAF3. Advances in experimental medicine and biology 16 17633021
2018 TRAF3-interacting protein 3, a new oncotarget, promotes tumor growth in melanoma. Melanoma research 15 29553967
2009 TRAF2 and TRAF3 independently mediate Ig class switching driven by CD40. International immunology 15 19228877
2002 Cell adhesion protects c-Raf-1 against ubiquitin-dependent degradation by the proteasome. Biochemical and biophysical research communications 15 12074572

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