Affinage

TRAF5

TNF receptor-associated factor 5 · UniProt O00463

Length
557 aa
Mass
64.4 kDa
Annotated
2026-04-28
78 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAF5 is a cytoplasmic adaptor and E3 ubiquitin ligase that transduces signals from TNF receptor superfamily members (LT-βR, CD40, CD27, OX40, CD30) and innate immune receptors (MAVS) to activate NF-κB, JNK/SAPK, and IRF3 pathways, functioning redundantly with TRAF2 in TNF-induced NF-κB activation and cell survival (PMID:8663299, PMID:11479302, PMID:20161788). Beyond canonical receptor signaling, TRAF5 constitutively associates with the IL-6 receptor subunit gp130 to inhibit JAK1 transphosphorylation and STAT3 activation, thereby limiting Th17 differentiation, while its RING-finger-dependent K63-linked ubiquitination of RORγt stabilizes this transcription factor in committed Th17 cells (PMID:24681564, PMID:29668931, PMID:26453305). TRAF5 also participates in IL-17-induced post-transcriptional regulation by forming Act1–TRAF2/TRAF5–SF2(ASF) and TRAF2/TRAF5/HuR complexes that stabilize chemokine and glycolytic enzyme mRNAs, and negatively regulates TLR signaling in B cells by sequestering TAB2 from TRAF6 (PMID:21822258, PMID:24259503, PMID:39944257). TRAF5 protein levels are controlled by Numbl-mediated K48-linked polyubiquitination and proteasomal degradation, and its mRNA is subject to METTL3-dependent m6A modification (PMID:22593207, PMID:33555197).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Identification of TRAF5 as a new TRAF family member that binds LT-βR and CD40 and activates NF-κB established it as a signal transducer for TNF receptor superfamily members, resolving which adaptor proteins mediate signaling from these receptors.

    Evidence In vitro binding, co-IP, NF-κB reporter and dominant-negative assays in HEK293/COS7 cells; yeast two-hybrid and CD23 surface expression for CD40

    PMID:8663299 PMID:8790348

    Open questions at the time
    • E3 ligase activity of RING domain not yet demonstrated
    • in vivo relevance not established
    • relationship to other TRAFs in same pathway unclear
  2. 1998 High

    Demonstration that TRAF5 mediates NF-κB and JNK activation downstream of CD27 and OX40 via NIK broadened its receptor repertoire and placed it upstream of NIK in the signaling cascade.

    Evidence Co-transfection with dominant-negative mutants, deletion mapping of receptor motifs, NF-κB and JNK reporter assays

    PMID:9488716 PMID:9582383

    Open questions at the time
    • redundancy with TRAF2 not genetically resolved
    • NIK as sole downstream kinase not confirmed in vivo
  3. 1999 High

    TRAF5-knockout mice revealed that TRAF5 is required for CD40-mediated B cell activation and CD27 costimulation in vivo, but NF-κB and JNK activation were not fully abolished, suggesting functional redundancy with TRAF2.

    Evidence Gene-targeted TRAF5-/- mice, B cell proliferation, surface marker flow cytometry, Ig production, NF-κB/JNK assays

    PMID:10449775

    Open questions at the time
    • double knockout with TRAF2 not yet generated
    • mechanism of compensation unknown
  4. 2001 High

    TRAF2/TRAF5 double-knockout MEFs demonstrated that both TRAFs are collectively essential for TNF-induced NF-κB nuclear translocation and protection from TNF-induced cell death, resolving the redundancy question.

    Evidence Double-knockout MEF generation, NF-κB nuclear translocation assay, cytotoxicity assay

    PMID:11479302

    Open questions at the time
    • specific biochemical contribution of TRAF5 versus TRAF2 to ubiquitination events unresolved
    • downstream kinase cascade not fully defined
  5. 2003 High

    Positioning TRAF2/TRAF5 upstream of TAK1→IKKα/IKKβ→p65 Ser-536 phosphorylation defined the linear kinase cascade through which these adaptors control NF-κB transcriptional activity, while a parallel finding showed TRAF5 is required for RANKL/TNF-induced osteoclastogenesis.

    Evidence DKO MEFs with anti-phospho-p65, siRNA, dominant-negatives; TRAF5-/- osteoclast progenitor cultures and PTH hypercalcemia model

    PMID:12619928 PMID:12842894

    Open questions at the time
    • direct E3 ligase substrates of TRAF5 in osteoclast pathway unknown
    • why JNK/NF-κB appear normal yet differentiation fails in osteoclasts is mechanistically unexplained
  6. 2009 High

    TRAF5 was shown to associate preferentially with the EBV oncoprotein LMP1 over CD40 and to be essential for LMP1-driven JNK signaling and B cell hyperactivation in vivo, linking TRAF5 to viral oncogenesis, while parallel work in DKO cells clarified that TRAF2 (not TRAF5) specifically recruits anti-apoptotic factors to TNFR1.

    Evidence Co-IP, transgenic/KO mouse crosses, JNK assays, B cell phenotyping; DKO IKK activity and TNFR1 complex analysis

    PMID:19409903 PMID:19805155

    Open questions at the time
    • structural basis of LMP1 preference for TRAF5 over CD40 unknown
    • TRAF5's specific ubiquitin-ligase targets in LMP1 signaling not identified
  7. 2010 Medium

    Discovery that TRAF5 is recruited to dimerized MAVS and mediates both IRF3 and NF-κB activation placed TRAF5 in the RIG-I antiviral innate immune pathway, expanding its role beyond TNF receptor family signaling.

    Evidence Co-IP, ubiquitination assays, IRF3/NF-κB reporters, MAVS domain-deletion analysis

    PMID:20161788

    Open questions at the time
    • ubiquitin linkage type on TRAF5 downstream of MAVS not specified
    • in vivo antiviral phenotype of TRAF5-/- mice not tested
    • single laboratory study
  8. 2011 High

    IL-17-induced mRNA stabilization of CXCL1 was shown to require an Act1→TRAF2/TRAF5→SF2(ASF) complex, revealing a post-transcriptional adaptor function for TRAF5 beyond kinase cascade signaling.

    Evidence mRNA half-life assays, siRNA knockdown of TRAF2/TRAF5, co-IP of TRAF5-TRAF2-Act1-SF2 complex, RNA-binding assays

    PMID:21822258

    Open questions at the time
    • whether TRAF5 directly contacts mRNA or acts solely as scaffold unknown
    • broader target mRNA repertoire not defined
  9. 2012 High

    Structural determination of the TRAF5 TRAF domain and identification of residues governing paralog-specific receptor binding provided a molecular framework for understanding TRAF5 versus TRAF3 functional divergence, while Numbl was identified as a K48-ubiquitin ligase targeting TRAF5 for degradation.

    Evidence Crystal structure, mutagenesis with IFN reporter; Co-IP, K48-linkage-specific ubiquitination assay, proteasome inhibitor rescue

    PMID:22593207 PMID:23150880

    Open questions at the time
    • full-length TRAF5 structure including RING domain not solved
    • Numbl-TRAF5 axis not validated in primary immune cells
  10. 2013 High

    TRAF5 was identified as a negative regulator of TLR-MyD88 signaling in B cells by sequestering TAB2 from TRAF6, demonstrating that TRAF5 can function as an inhibitory adaptor depending on pathway context.

    Evidence TRAF5-/- B cell cytokine and MAPK assays, Co-IP of TRAF5-MyD88-TAB2 complex, overexpression rescue

    PMID:24259503

    Open questions at the time
    • ubiquitin-dependent or -independent mechanism of TAB2 sequestration unclear
    • whether this negative role extends to other cell types not tested
  11. 2014 High

    Constitutive TRAF5-gp130 association that blocks STAT3 recruitment and limits Th17 differentiation revealed a tonic inhibitory role for TRAF5 in IL-6 signaling, with EAE exacerbation in TRAF5-/- mice demonstrating in vivo disease relevance.

    Evidence Constitutive Co-IP of TRAF5-gp130, STAT3 phosphorylation in KO T cells, in vitro Th17 differentiation, EAE model

    PMID:24681564

    Open questions at the time
    • stoichiometry of TRAF5 on gp130 in resting versus activated cells not determined
    • whether other gp130-using cytokines (IL-27, OSM) are similarly regulated unknown
  12. 2015 High

    TRAF5's RING-finger-dependent K63-linked ubiquitination of RORγt that stabilizes the protein established the first direct E3 ligase substrate of TRAF5 in Th17 biology, reconciling its dual roles as both a gp130-inhibitor (limiting Th17 initiation) and a RORγt stabilizer (promoting Th17 effector function).

    Evidence Co-IP, K63-specific ubiquitination assay, RING domain mutagenesis, TRAF5 knockdown with RORγt protein quantification and Th17 gene expression

    PMID:26453305

    Open questions at the time
    • specific lysine residue(s) on RORγt ubiquitinated by TRAF5 not mapped
    • whether K63-Ub of RORγt prevents K48-Ub or acts through another stabilization mechanism unknown
  13. 2018 High

    Demonstration that TRAF5 binding to gp130 inhibits JAK1-JAK1 transphosphorylation provided the proximal molecular mechanism for TRAF5's tonic suppression of IL-6 signaling, refining the 2014 model from STAT3-level to JAK1-level inhibition.

    Evidence Luciferase fragment complementation for JAK1-JAK1 interaction, co-transfection with gp130/TRAF chimeras, JAK1 phosphorylation in Traf5-/- T cells

    PMID:29668931

    Open questions at the time
    • structural model of how TRAF5 sterically blocks JAK1 proximity not available
    • whether TRAF2 contributes additively at this step in primary T cells not fully resolved
  14. 2020 High

    Multiple tissue-specific roles emerged: 14-3-3ζ was identified as a TRAF5 interactor that relieves TRAF5-mediated suppression of IL-17A→IL-6 signaling; TRAF5 was shown to promote AKT activation protecting cardiomyocytes from ischemia-reperfusion injury; and TRAF5 was found to stabilize TRAF2 protein in colonic cells during inflammation.

    Evidence Co-IP in multiple systems, TRAF5-KO mouse I/R and DSS colitis models, bone marrow chimeras, proteasome inhibitor experiments, AKT phosphorylation

    PMID:32156688 PMID:32234528 PMID:32968020

    Open questions at the time
    • whether AKT activation is direct or indirect through NF-κB not resolved
    • mechanism by which TRAF5 stabilizes TRAF2 protein not defined at molecular level
    • 14-3-3ζ binding site on TRAF5 not mapped
  15. 2024 Medium

    IL-17A was shown to drive formation of a TRAF2/TRAF5/HuR complex that stabilizes PFKFB3 mRNA to promote glycolysis and hepatic stellate cell fibrosis, extending TRAF5's post-transcriptional adaptor role to metabolic gene regulation.

    Evidence Co-IP, RNA immunoprecipitation, RNA pull-down, ECAR glycolysis measurement, siRNA knockdown

    PMID:39944257

    Open questions at the time
    • whether TRAF5 E3 ligase activity is required for HuR complex formation unknown
    • in vivo liver fibrosis rescue by TRAF5 depletion not tested
    • single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the full substrate repertoire of TRAF5's E3 ubiquitin ligase activity, the structural basis for how gp130-bound TRAF5 blocks JAK1 proximity, whether TRAF5's post-transcriptional mRNA-stabilizing role extends to a broader transcriptome, and how the opposing pro-inflammatory (NF-κB activation) and anti-inflammatory (TLR inhibition, gp130 suppression) activities of TRAF5 are contextually regulated in different cell types.
  • full-length TRAF5 structure not solved
  • comprehensive substrate identification for RING E3 activity lacking
  • cell-type-specific regulatory switches between positive and negative signaling roles not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CD40IL6STLTBRMAVSNUMBRORCTRAF2YWHAZ
Complex memberships
Act1-TRAF2/TRAF5-SF2(ASF)TRAF2/TRAF5/HuR

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 TRAF5 was identified as a novel TRAF family member containing a zinc RING finger, zinc finger motifs, a coiled-coil region, and a C-terminal TRAF homology domain. In vitro translated TRAF5 binds to the cytoplasmic region of the lymphotoxin-beta receptor (LT-βR). Overexpression of full-length TRAF5 (but not a truncated form lacking the zinc binding region) activates NF-κB in HEK293 cells, and a truncated dominant-negative TRAF5 partially inhibits LT-βR-mediated NF-κB activation. In vitro binding assay, co-immunoprecipitation in COS7 cells, NF-κB reporter assay with dominant-negative mutants The Journal of biological chemistry High 8663299
1996 TRAF5 associates with the cytoplasmic tail of CD40 (residues 230-269 required), identified by yeast two-hybrid and in vitro binding assay. Overexpression of TRAF5 activates NF-κB, and amino-terminally truncated TRAF5 suppresses CD40-mediated induction of CD23 expression. Yeast two-hybrid, in vitro binding assay, NF-κB reporter assay, CD23 surface expression assay Proceedings of the National Academy of Sciences of the United States of America High 8790348
1998 CD27 activates NF-κB and SAPK/JNK via TRAF2 and TRAF5. The C-terminal PIQEDYR motif of CD27 is required for interaction with TRAF2 and TRAF5. Dominant-negative TRAF2 or TRAF5 blocked both NF-κB and SAPK/JNK activation. NF-κB-inducing kinase (NIK) is a downstream kinase common to both TRAF2 and TRAF5 in this pathway. Co-transfection, dominant-negative mutants, deletion analysis, NF-κB/JNK reporter assays The Journal of biological chemistry High 9582383
1998 TRAF1, TRAF2, TRAF3, and TRAF5 (but not TRAF4) associate with OX40 in vitro and in vivo; the cytoplasmic amino acids 256-263 (GGSFRTPI) of OX40 are required. Dominant-negative TRAF2 and TRAF5 suppress OX40-induced NF-κB activation in a dose-dependent manner. TRAF3 negatively modulates OX40-mediated NF-κB activation. GST pulldown, co-transfection Co-IP, deletion analysis, NF-κB reporter assay with dominant-negative mutants The Journal of biological chemistry High 9488716
1999 TRAF5-deficient mice show that TRAF5 is required for CD40-mediated B cell proliferation, upregulation of CD23, CD54, CD80, CD86, and Fas, and in vitro Ig production. CD27-mediated costimulatory signaling is also impaired in TRAF5-deficient T cells. However, NF-κB and JNK/SAPK activation by TNF, CD27, and CD40 were not fully abrogated in single TRAF5 knockout cells. Gene targeting (knockout mice), B cell proliferation assays, flow cytometry surface marker analysis, Ig production assay, NF-κB and JNK activation assays Proceedings of the National Academy of Sciences of the United States of America High 10449775
2001 TRAF2 and TRAF5 double knockout (DKO) MEFs show severely impaired TNF-induced (but not IL-1-induced) NF-κB nuclear translocation and are more susceptible to TNF-induced cytotoxicity than single TRAF2 knockout MEFs, demonstrating both TRAF2 and TRAF5 are required for TNF-induced NF-κB activation and protection from cell death. Double knockout mice generation, NF-κB nuclear translocation assay, cell viability/cytotoxicity assay The Journal of biological chemistry High 11479302
2001 Activation of TRAF5 (and TRAF6) signal cascades suppresses EBV latent replication origin (oriP) activity through p38 MAPK. The TRAF binding site of LMP1 mediates this suppression. Dominant-negative TRAF5 and TRAF6 mutants release LMP1-induced oriP suppression, and p38 MAPK inhibition abolishes this effect. Transient replication assay, overexpression/dominant-negative mutants, p38 MAPK inhibitor Journal of virology Medium 11333886
2002 TRAF2 and TRAF5 form cytoplasmic aggregates in Hodgkin-Reed-Sternberg cells overexpressing CD30, co-localizing with IKKα, NIK, and IκBα. Dominant-negative TRAF2 and TRAF5 suppress cytoplasmic aggregation and constitutive NF-κB activation, suggesting TRAF proteins function as scaffolding proteins in CD30 signaling. Confocal immunofluorescence microscopy, dominant-negative overexpression, NF-κB activity assay The American journal of pathology Medium 12000717
2003 TNF-α-induced phosphorylation of NF-κB p65 on Ser-536 is severely impaired in TRAF2/TRAF5 double knockout MEFs, and involves the TRAF2/TRAF5→TAK1→IKKα/IKKβ signaling pathway. Overexpression of TAK1, IKKα, IKKβ stimulates p65 Ser-536 phosphorylation; their dominant-negative mutants and siRNAs block it. Nuclear dephosphorylation is mediated by a protein phosphatase. Double-knockout MEFs, anti-phospho-p65 antibody, siRNA, dominant-negative mutants, pharmacological inhibitors The Journal of biological chemistry High 12842894
2003 TRAF5 is required for efficient RANKL- and TNFα-induced osteoclastogenesis. Osteoclast progenitors from TRAF5-deficient mice fail to differentiate effectively into mature multinucleated osteoclasts in response to RANKL or TNFα, and PTH-induced hypercalcemia peak is delayed, despite normal JNK and NF-κB activation in progenitors. Knockout mouse-derived osteoclast progenitor cultures, osteoclast differentiation assays, PTH-induced hypercalcemia model in vivo Journal of bone and mineral research High 12619928
2009 TRAF5 associates strongly with the viral oncogenic CD40 mimic LMP1 (more strongly than with CD40 itself). TRAF5 plays a critical role in LMP1-mediated c-Jun kinase signaling and is required for the abnormal B cell hyperactivation phenotype (splenomegaly, lymphadenopathy, elevated IL-6, autoantibodies) in mCD40LMP1 transgenic mice. Co-immunoprecipitation, transgenic/knockout mouse crosses, JNK signaling assays, in vivo B cell phenotyping Proceedings of the National Academy of Sciences of the United States of America High 19805155
2009 In TRAF2/TRAF5 double-knockout cells, TNF-induced RIP1 ubiquitination is impaired, yet basal IKK activity is elevated due to NIK. TNFα can still further activate IKK in DKO cells. TRAF2 (not TRAF5) is specifically required for recruitment of anti-apoptotic proteins to the TNFR1 complex, which is the mechanism protecting cells from TNF-induced death. Double-knockout cell analysis, IKK activity assay, NIK inhibition, TNFR1 complex immunoprecipitation, NF-κB target gene expression Journal of molecular biology High 19409903
2010 TRAF5 is a downstream target of MAVS in antiviral innate immune signaling. The TM domain of MAVS allows dimerization, leading to TRAF5 association and ubiquitination of TRAF5 in a CARD-dependent manner. TRAF5 mediates both IRF3 and NF-κB activation downstream of MAVS. NEMO is recruited to dimerized MAVS CARD in a TRAF3- and TRAF5-dependent manner. Co-immunoprecipitation, ubiquitination assays, reporter assays for IRF3/NF-κB, domain-deletion analysis PloS one Medium 20161788
2010 TRAF5 deficiency in mice accelerates atherosclerosis; TRAF5-deficient endothelial cells and leukocytes show enhanced adhesion molecule/chemokine expression and increased macrophage lipid uptake/foam cell formation, associated with increased JNK activation and apparently independent of TRAF2. TRAF5-/-/LDLR-/- mice on high-cholesterol diet, intravital microscopy, dynamic adhesion assays, flow cytometry, JNK activity assays Circulation research High 20651286
2011 IL-17 promotes CXCL1 mRNA stability through Act1→TRAF2/TRAF5→SF2(ASF) pathway. TRAF2 and TRAF5 are necessary for IL-17-induced CXCL1 mRNA stabilization. IL-17 promotes formation of TRAF5-TRAF2-Act1-SF2(ASF) complexes. SF2(ASF) binds chemokine mRNA in unstimulated cells, and this interaction is reduced after IL-17 stimulation. mRNA half-life assay, siRNA knockdown, co-immunoprecipitation, RNA-binding protein interaction assay Nature immunology High 21822258
2012 TRAF5 crystal structure (TRAF domain) was solved, and structural comparison with TRAF3 identified two residues (Tyr440 and Phe473 in TRAF3) near the Cardif-binding pocket. Mutation of the corresponding TRAF5 residues to those of TRAF3 conferred TRAF3-like antiviral (RIG-I/Cardif-mediated IFN-inducing) activity on TRAF5 in vitro and in cells. Crystal structure determination, in vitro binding assay, mutagenesis, cellular IFN reporter assay Science signaling High 23150880
2012 Numbl interacts directly with TRAF5 and promotes K48-linked polyubiquitination of TRAF5, committing it to proteasomal degradation, thereby suppressing TRAF5-induced NF-κB activation and inhibiting glioma cell migration and invasion. Co-immunoprecipitation, ubiquitination assay (K48-linkage specificity), proteasome inhibitor, overexpression/knockdown, NF-κB reporter, migration/invasion assays Molecular biology of the cell High 22593207
2013 TRAF5 is a negative regulator of TLR signaling in B lymphocytes. Following TLR stimulation, TRAF5 associates in a complex with MyD88 and TAB2, and negatively regulates the association of TAB2 with TRAF6. TRAF5-deficient B cells produce more cytokines and show enhanced ERK1/2 and JNK phosphorylation without effects on NF-κB or cell survival. TRAF5 knockout mice, cytokine measurements, co-immunoprecipitation, MAPK phosphorylation assays, overexpression in B cells Journal of immunology High 24259503
2014 TRAF5 constitutively associates with the cytoplasmic region of gp130 (overlapping the STAT3 binding site) and suppresses IL-6-induced STAT3 recruitment and activation, thereby limiting TH17 differentiation. TRAF5-deficient naive CD4+ T cells show enhanced TH17 differentiation in the presence of IL-6, and EAE is exaggerated in Traf5-/- mice. Co-immunoprecipitation (constitutive TRAF5-gp130 association), knockout mouse T cell differentiation assay, STAT3 phosphorylation, EAE model Nature immunology High 24681564
2015 TRAF5 interacts with RORγt and promotes Lys-63-linked polyubiquitination of RORγt via its RING finger domain, stabilizing RORγt protein. Depletion of TRAF5 in Th17 cells destabilizes RORγt and downregulates IL-17A and other Th17-related genes. Co-immunoprecipitation, ubiquitination assay (K63-linkage), RING finger domain mutagenesis, TRAF5 knockdown, qRT-PCR for Th17 genes The Journal of biological chemistry High 26453305
2016 TRAF5 peptide-binding specificity was characterized by deep mutational scanning of peptide libraries displayed on E. coli. TRAF5's MATH domain shows different binding preferences from TRAF2 and TRAF3 for CD40- and TANK-derived peptides, demonstrating a previously unappreciated level of paralog-specific binding selectivity. Deep mutational scanning, bacterial surface display, high-throughput sequencing enrichment analysis, individual peptide affinity measurements Protein science High 26779844
2016 TRAF5 deficiency in hepatocytes leads to worsened nonalcoholic fatty liver disease (NAFLD/NASH) in HFD and ob/ob mice. Mechanistically, TRAF5 negatively regulates Jnk1 (but not Jnk2) activity; Jnk1 ablation rescues the detrimental effects of TRAF5 deficiency on obesity, inflammation, insulin resistance, hepatic steatosis, and fibrosis. Gain/loss-of-function in vivo (adenoviral TRAF5 overexpression, TRAF5-knockout, Jnk1/Jnk2 ablation), metabolic phenotyping, JNK activity assays Journal of hepatology High 27032381
2018 TRAF2 and TRAF5 constitutively associated with gp130 inhibit IL-6-driven transphosphorylation of JAK1 by limiting proximal JAK1-JAK1 interaction in the IL-6R complex. The C-terminal TRAF domain binding to gp130 is essential for this inhibition. Traf5-/- CD4+ T cells show significantly higher phosphorylated JAK1 than wild-type after IL-6 stimulation. Luciferase fragment complementation system for JAK1-JAK1 interaction, co-transfection of gp130/TRAFs/JAK1 chimeras, JAK1 phosphorylation in Traf5-/- T cells International immunology High 29668931
2020 14-3-3ζ interacts with TRAF5 and TRAF6, and this interaction increases in the presence of IL-17A. TRAF5 acts as an endogenous suppressor of IL-17A-induced IL-6 production, and 14-3-3ζ counters TRAF5's suppressive effect. The 14-3-3ζ-TRAF5 axis differentially regulates IL-17A-induced IL-6 and CXCL-1 production. Co-immunoprecipitation, genetically manipulated human and mouse cells, ex vivo and in vivo rat models, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America High 32968020
2020 TRAF5 promotes AKT signaling activation in cardiomyocytes. TRAF5 knockout mice exhibit more severe myocardial ischemia/reperfusion injury, inflammation, and cell death. TRAF5 overexpression inhibits inflammation and apoptosis in hypoxia/reoxygenation-stimulated cardiomyocytes by promoting AKT activation. TRAF5 knockout mice, I/R injury model, AKT phosphorylation assay, overexpression/knockdown in cardiomyocytes, cell viability assays European journal of pharmacology Medium 32234528
2020 TRAF5 deficiency in nonhematopoietic colonic cells leads to reduced TRAF2 protein stability in the inflamed colon (via proteasome-dependent degradation), resulting in attenuated DSS-induced colitis. This demonstrates a novel role for TRAF5 in maintaining TRAF2 protein levels and its proinflammatory function. TRAF5 knockout mice, bone marrow chimeras, DSS colitis model, TRAF2 protein quantification, proteasome inhibitor experiments ImmunoHorizons Medium 32156688
2021 TRAF5 is regulated by METTL3-mediated m6A modification. In colorectal cancer cells resistant to oxaliplatin, METTL3-mediated m6A modification of TRAF5 mRNA contributes to OX resistance, established via whole-genome CRISPR screening and validation. CRISPR screen, m6A measurement, METTL3 overexpression/knockdown, TRAF5 manipulation Molecular pharmaceutics Medium 33555197
2023 TRAF5 silencing inhibits HCC cell viability and promotes necroptosis. TRAF5 interacts with LTBR (lymphotoxin-beta receptor) and positively regulates LTBR expression and downstream NF-κB signaling, protecting cancer cells from necroptosis. LTBR overexpression abolishes the pro-necroptotic effect of TRAF5 knockdown. Co-immunoprecipitation, immunofluorescence, knockdown, overexpression, xenograft model, NF-κB signaling assays, necroptosis markers (p-RIP1, p-MLKL) PeerJ Medium 37366426
2024 IL-17A promotes formation of a TRAF2/TRAF5/HuR complex (validated by co-IP, RIP, and RNA pull-down), which enhances PFKFB3 mRNA expression and promotes glycolysis and fibrosis of hepatic stellate cells. TRAF2 and TRAF5 silencing abolishes this IL-17A-mediated glycolytic effect. Co-immunoprecipitation, RNA immunoprecipitation (RIP), RNA pull-down, ECAR measurement, siRNA knockdown Central-European journal of immunology Medium 39944257
2025 Huwe1 (a HECT-domain ubiquitin E3 ligase) interacts with TRAF5 and is essential for TRAF5 activity in type I IFN induction downstream of RIG-I-like receptors. Loss of Huwe1 attenuates IFN-β/IFN-λ1 and ISG expression, and TRAF5 is identified as a key Huwe1 substrate via proteomics. Proteomics (substrate identification), co-immunoprecipitation, genetic loss-of-function (Huwe1 depletion), IFN reporter assays bioRxivpreprint Medium bio_10.1101_2025.03.27.645708

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Tumor necrosis factor-alpha-induced IKK phosphorylation of NF-kappaB p65 on serine 536 is mediated through the TRAF2, TRAF5, and TAK1 signaling pathway. The Journal of biological chemistry 324 12842894
1996 TRAF5, an activator of NF-kappaB and putative signal transducer for the lymphotoxin-beta receptor. The Journal of biological chemistry 304 8663299
1996 TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling. Proceedings of the National Academy of Sciences of the United States of America 303 8790348
2001 Critical roles of TRAF2 and TRAF5 in tumor necrosis factor-induced NF-kappa B activation and protection from cell death. The Journal of biological chemistry 256 11479302
1998 CD27, a member of the tumor necrosis factor receptor superfamily, activates NF-kappaB and stress-activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-kappaB-inducing kinase. The Journal of biological chemistry 216 9582383
2011 Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF). Nature immunology 203 21822258
1998 Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation. The Journal of biological chemistry 164 9488716
1999 Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activation. Proceedings of the National Academy of Sciences of the United States of America 152 10449775
1997 ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5. The Journal of biological chemistry 148 9153189
2011 Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions. Immunological reviews 90 22017431
2021 Tumor-Associated Macrophages Promote Oxaliplatin Resistance via METTL3-Mediated m6A of TRAF5 and Necroptosis in Colorectal Cancer. Molecular pharmaceutics 89 33555197
2019 MiR-141-3p inhibits cell proliferation, migration and invasion by targeting TRAF5 in colorectal cancer. Biochemical and biophysical research communications 72 31078266
2012 Numbl inhibits glioma cell migration and invasion by suppressing TRAF5-mediated NF-κB activation. Molecular biology of the cell 70 22593207
2010 TRAF5 is a downstream target of MAVS in antiviral innate immune signaling. PloS one 70 20161788
2018 Astragaloside IV/lncRNA-TUG1/TRAF5 signaling pathway participates in podocyte apoptosis of diabetic nephropathy rats. Drug design, development and therapy 69 30233141
2007 Physiological roles and mechanisms of signaling by TRAF2 and TRAF5. Advances in experimental medicine and biology 66 17633015
2003 TRAF5 functions in both RANKL- and TNFalpha-induced osteoclastogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 52 12619928
2002 Cytoplasmic aggregation of TRAF2 and TRAF5 proteins in the Hodgkin-Reed-Sternberg cells. The American journal of pathology 52 12000717
2010 TRAF5 deficiency accelerates atherogenesis in mice by increasing inflammatory cell recruitment and foam cell formation. Circulation research 49 20651286
2013 TRAF5 negatively regulates TLR signaling in B lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 47 24259503
2016 Tumor necrosis factor receptor-associated factor 5 (Traf5) acts as an essential negative regulator of hepatic steatosis. Journal of hepatology 45 27032381
2015 TRAF5-mediated Lys-63-linked Polyubiquitination Plays an Essential Role in Positive Regulation of RORγt in Promoting IL-17A Expression. The Journal of biological chemistry 43 26453305
2020 LINC00467 promotes cell proliferation and metastasis by binding with IGF2BP3 to enhance the mRNA stability of TRAF5 in hepatocellular carcinoma. The journal of gene medicine 40 31656043
2018 Astragaloside suppresses apoptosis of the podocytes in rats with diabetic nephropathy via miR-378/TRAF5 signaling pathway. Life sciences 38 29792879
2014 The adaptor TRAF5 limits the differentiation of inflammatory CD4(+) T cells by antagonizing signaling via the receptor for IL-6. Nature immunology 38 24681564
2013 HIV-1 Nef interacts with HCV Core, recruits TRAF2, TRAF5 and TRAF6, and stimulates HIV-1 replication in macrophages. Journal of innate immunity 37 23774506
2012 Single amino acid substitutions confer the antiviral activity of the TRAF3 adaptor protein onto TRAF5. Science signaling 37 23150880
2016 MiR-26b inhibits melanoma cell proliferation and enhances apoptosis by suppressing TRAF5-mediated MAPK activation. Biochemical and biophysical research communications 34 26872428
2009 TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40. Proceedings of the National Academy of Sciences of the United States of America 34 19805155
2019 Upregulation of miR-29b-3p protects cardiomyocytes from hypoxia-induced apoptosis by targeting TRAF5. Cellular & molecular biology letters 31 31011336
2009 TRAF2 suppresses basal IKK activity in resting cells and TNFalpha can activate IKK in TRAF2 and TRAF5 double knockout cells. Journal of molecular biology 30 19409903
2022 LncRNA HCG18 upregulates TRAF4/TRAF5 to facilitate proliferation, migration and EMT of epithelial ovarian cancer by targeting miR-29a/b. Molecular medicine (Cambridge, Mass.) 27 34983361
2019 miR-135a suppresses migration of gastric cancer cells by targeting TRAF5-mediated NF-κB activation. OncoTargets and therapy 27 30774383
2016 MicroRNA-26b regulates cancer proliferation migration and cell cycle transition by suppressing TRAF5 in esophageal squamous cell carcinoma. American journal of translational research 27 27347306
2018 miR‑873 inhibits colorectal cancer cell proliferation by targeting TRAF5 and TAB1. Oncology reports 26 29328486
2014 TRAF5 and TRAF3IP2 gene polymorphisms are associated with Behçet's disease and Vogt-Koyanagi-Harada syndrome: a case-control study. PloS one 26 24416204
2020 Circ_0010729 regulates hypoxia-induced cardiomyocyte injuries by activating TRAF5 via sponging miR-27a-3p. Life sciences 24 33010282
2016 Comparison of the peptide binding preferences of three closely related TRAF paralogs: TRAF2, TRAF3, and TRAF5. Protein science : a publication of the Protein Society 23 26779844
2021 Downregulation of long noncoding RNA SNHG7 protects against inflammation and apoptosis in Parkinson's disease model by targeting the miR-425-5p/TRAF5/NF-κB axis. Journal of biochemical and molecular toxicology 22 34369042
2013 Up-regulation and pre-activation of TRAF3 and TRAF5 in inflammatory bowel disease. International journal of medical sciences 21 23329887
2024 CD36 deletion prevents white matter injury by modulating microglia polarization through the Traf5-MAPK signal pathway. Journal of neuroinflammation 19 38840180
2020 TRAF5 protects against myocardial ischemia reperfusion injury via AKT signaling. European journal of pharmacology 18 32234528
2020 14-3-3ζ-TRAF5 axis governs interleukin-17A signaling. Proceedings of the National Academy of Sciences of the United States of America 18 32968020
2020 LncRNA CDKN2B-AS1 contributes to tumorigenesis and chemoresistance in pediatric T-cell acute lymphoblastic leukemia through miR-335-3p/TRAF5 axis. Anti-cancer drugs 18 32976214
2020 Down-regulated HDAC3 elevates microRNA-495-3p to restrain epithelial-mesenchymal transition and oncogenicity of melanoma cells via reducing TRAF5. Journal of cellular and molecular medicine 17 33048450
2023 PCSK9 inhibitor attenuates atherosclerosis by regulating SNHG16/EZH2/TRAF5-mediated VSMC proliferation, migration, and foam cell formation. Cell biology international 15 37017413
2001 Activation of TRAF5 and TRAF6 signal cascades negatively regulates the latent replication origin of Epstein-Barr virus through p38 mitogen-activated protein kinase. Journal of virology 15 11333886
1998 Cloning and characterization of a cDNA encoding the human homolog of tumor necrosis factor receptor-associated factor 5 (TRAF5). Gene 15 9511754
2019 miR-141-3p and TRAF5 Network Contributes to the Progression of T-Cell Acute Lymphoblastic Leukemia. Cell transplantation 14 31722554
1997 Human TNF receptor-associated factor 5 (TRAF5): cDNA cloning, expression and assignment of the TRAF5 gene to chromosome 1q32. Genomics 13 9177772
2021 Silenced lncRNA DDX11-AS1 or up-regulated microRNA-34a-3p inhibits malignant phenotypes of hepatocellular carcinoma cells via suppression of TRAF5. Cancer cell international 12 33752668
2019 Overexpression of miRNA-410-3p protects hypoxia-induced cardiomyocyte injury via targeting TRAF5. European review for medical and pharmacological sciences 11 31696495
2021 Association of methylation level and transcript level in TRAF5 gene with ankylosing spondylitis: a case-control study. Genes and immunity 10 34021268
2021 HP1BP3 promotes tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal squamous cell carcinoma. American journal of cancer research 10 34249436
2017 Berberine prevents the apoptosis of mouse podocytes induced by TRAF5 overexpression by suppressing NF-κB activation. International journal of molecular medicine 10 29115406
2023 TRAF5 regulates intestinal mucosal Th1/Th17 cell immune responses via Runx1 in colitis mice. Immunology 9 37575027
2021 Genetic Deficiency of TRAF5 Promotes Adipose Tissue Inflammation and Aggravates Diet-Induced Obesity in Mice. Arteriosclerosis, thrombosis, and vascular biology 9 34348490
2019 Effects of antisense lncRNA PCBP1-AS1 on biological behaviors of vulvar squamous carcinoma cells by regulating TRAF5 and NF-κB expression. Translational cancer research 8 35116901
2021 Grouper TRAF5 exerts negative regulation on antiviral immune response against iridovirus. Fish & shellfish immunology 7 34062236
2018 TRAF2 and TRAF5 associated with the signal transducing receptor gp130 limit IL-6-driven transphosphorylation of JAK1 through the inhibition of proximal JAK-JAK interaction. International immunology 7 29668931
2023 Silencing of TRAF5 enhances necroptosis in hepatocellular carcinoma by inhibiting LTBR-mediated NF-κB signaling. PeerJ 6 37366426
2022 TRAF5 splicing variants associate with TRAF3 and RIP1 in NF-κB and type I IFN signaling in large yellow croaker Larimichthys crocea. Fish & shellfish immunology 6 36152803
2020 The fiber metabolite butyrate reduces gp130 by targeting TRAF5 in colorectal cancer cells. Cancer cell international 6 32518521
2020 TRAF5 promotes the occurrence and development of colon cancer via the activation of PI3K/AKT/NF-κB signaling pathways. Journal of biological regulators and homeostatic agents 6 32911926
2021 Single nucleotide polymorphisms of TRAF2 and TRAF5 gene in ankylosing spondylitis: a case-control study. Clinical and experimental medicine 5 33997937
2015 Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5. Biochemical and biophysical research communications 5 26454171
2023 METTL3-mediated m6 A methylation of TRAF5 inhibits lung adenocarcinoma cell metastasis via activation of the PI3K/AKT/NF-κB signaling pathway. The Kaohsiung journal of medical sciences 4 38088510
2020 Structural and biochemical characterization of TRAF5 from Notothenia coriiceps and its implications in fish immune cell signaling. Fish & shellfish immunology 4 32283248
2025 Exploring the Anti-Colorectal Cancer Mechanism of Norcantharidin Through TRAF5/NF-κB Pathway Regulation and Folate-Targeted Liposomal Delivery. International journal of molecular sciences 3 40003916
2024 Interleukin 17A promotes glycolysis to activate human hepatic stellate cells by mediating the TRAF2/TRAF5/HuR/PFKFB3 axis. Central-European journal of immunology 3 39944257
2023 Identification of necroptosis-related gene TRAF5 as potential target of diagnosing atherosclerosis and assessing its stability. BMC medical genomics 3 37330462
2020 TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells. ImmunoHorizons 3 32156688
2019 TRAF5 promotes plasmacytoid dendritic cell development from bone marrow progenitors. Biochemical and biophysical research communications 3 31668809
2025 Lithocholic acid attenuates DON-induced inflammatory responses via epigenetic regulation of DUSP5 and TRAF5 in porcine intestinal epithelial cells. Frontiers in veterinary science 2 40093618
2025 MicroRNA-18b-5p Inhibits the Malignant Progression of Prostate Cancer Through Downregulating TRAF5. International journal of general medicine 0 40191236
2025 Defective IgG Class Switching in the Spleen of TRAF5-Deficient Mice Reveals a Role for TRAF5 in CD40-Mediated B Cell Responses During Obesity-Associated Inflammation. International journal of molecular sciences 0 41096757
2025 PGC1α alleviates M1 macrophage polarization through dual regulation of succinate metabolism and TRAF5 expression to mitigate TLR4/NF-κB-driven inflammatory cascades and myocardial ischemia/reperfusion injury. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 0 41196309
2025 Rare TRAF5 coding variants in systemic lupus erythematosus patients aggravate pulmonary hypertension via endothelial dysfunction. Innovation (Cambridge (Mass.)) 0 41658503