| Aspect | Key points | Best recent sources with year and URL |
|---|---|---|
| Identity/domains | • Human **TRAF6 / TNF receptor-associated factor 6** matches UniProt Q9Y4K3 context • TRAF-family adaptor and **E3 ubiquitin ligase** • Domain architecture: **N-terminal RING**, multiple **zinc fingers**, **coiled-coil/TRAF-N**, **C-terminal TRAF-C/MATH** receptor-binding domain • TRAF-C recognizes receptor motifs; trimeric TRAF-C and stalk-like TRAF-N are emphasized in recent structural summaries (pqac-00000001, pqac-00000003, pqac-00000004, pqac-00000005) | Li et al., 2024, *Journal of Cancer* — https://doi.org/10.7150/jca.90059 ; Yang et al., 2025, *Frontiers in Physiology* — https://doi.org/10.3389/fphys.2025.1527814 ; Wu et al., 2024, *Marine Drugs* — https://doi.org/10.3390/md22060260 |
| Enzymatic activity | • TRAF6 functions as a **RING-type E3 ubiquitin ligase** and signaling scaffold • Works with E1/E2 enzymes to assemble signaling-active ubiquitin chains • Central output is activation of **TAK1/IKK → NF-κB** and **MAPK** signaling • Recent reviews also note TRAF6 can participate in both non-degradative signaling and degradative ubiquitin control depending on chain type/context (pqac-00000000, pqac-00000001, pqac-00000004, pqac-00000005) | Li et al., 2024 — https://doi.org/10.7150/jca.90059 ; Wu et al., 2024 — https://doi.org/10.3390/md22060260 |
| Key E2 partners | • Best-supported E2 complex is **Ubc13/UBE2N–Uev1A/UBE2V1** • This partnership is specifically linked to TRAF6-catalyzed **K63-linked polyubiquitination** • A recent inhibitor-development paper highlights a defined TRAF6–Ubc13 interaction surface including **Gln54, Asp57, Ile72, Leu74** on TRAF6 • Ubc13/Uev1A is also used in in vitro condensate reconstitution assays for TRAF6-driven ubiquitin-chain synthesis (pqac-00000001, pqac-00000005, pqac-00000020, pqac-00000022) | Li et al., 2024 — https://doi.org/10.7150/jca.90059 ; Wu et al., 2024 — https://doi.org/10.3390/md22060260 ; Li et al., 2024, *Research* — https://doi.org/10.34133/research.0315 |
| Ubiquitin linkage specificity | • **K63-linked chains** are the canonical TRAF6 signaling output and act as scaffolds rather than degradation tags • Representative K63-modified targets mentioned in recent review pages include **IKKγ/NEMO, TAK1, IRAK1, and TRAF6 itself** • Recent reviews also note TRAF6 can participate in **K48-linked** ubiquitination in some contexts, supporting proteasomal degradation/regulatory turnover • LLPS work links TRAF6 condensates to synthesis/retention of **long K63 polyUb chains** (pqac-00000001, pqac-00000004, pqac-00000020, pqac-00000021, pqac-00000022) | Li et al., 2024 — https://doi.org/10.7150/jca.90059 ; Li et al., 2024, *Research* — https://doi.org/10.34133/research.0315 |
| Representative substrates | • Recent review pages list **IKKγ/NEMO, TAK1, IRAK1, and TRAF6 itself** as representative K63-ubiquitinated targets/substrates in TRAF6 signaling • TRAF6 is also described as binding **p62** to ubiquitinate **mTOR**, linking it to growth/autophagy regulation • In disease-focused primary work, TRAF6 directly engages receptor/adaptor complexes such as **RANK** and **TIFA**, and viral protein **LMP1** recruits TRAF6 as a critical host effector • Evidence base is strongest for receptor-proximal signaling substrates/adaptors rather than a single exclusive substrate class (pqac-00000000, pqac-00000001, pqac-00000006, pqac-00000007) | Li et al., 2024 — https://doi.org/10.7150/jca.90059 ; Ayyasamy et al., 2024, *JBC* — https://doi.org/10.1016/j.jbc.2024.107487 ; Giehler et al., 2024, *Nature Communications* — https://doi.org/10.1038/s41467-023-44455-w |
| Core pathways | • Major pathways in recent evidence: **TLR/IL-1R–MyD88–IRAK–TRAF6–TAK1–NF-κB/MAPK** • **RANK/RANKL–TRAF6** is central for osteoclastogenesis and bone remodeling • Additional pathways in recent review/primary papers include **CD40/TRAF6-related signaling**, **IL-17R via Act1**, **TCR via CARMA1–BCL10–MALT1**, **TLR7/8/9–MYD88–IRF7**, and **ALPK1–TIFA–TRAF6** innate sensing • In EBV biology, **LMP1–TRAF6** drives NF-κB/JNK/p38/IRF7 signaling and lymphoma survival (pqac-00000001, pqac-00000006, pqac-00000007, pqac-00000023) | Li et al., 2024 — https://doi.org/10.7150/jca.90059 ; Ayyasamy et al., 2024 — https://doi.org/10.1016/j.jbc.2024.107487 ; Giehler et al., 2024 — https://doi.org/10.1038/s41467-023-44455-w ; Li et al., 2024 — https://doi.org/10.34133/research.0315 |
| Localization/complexes | • TRAF6 is a **cytosolic adaptor/E3** that assembles on **cytoplasmic tails of transmembrane receptors** and receptor-proximal signaling complexes • Recent primary data show dynamic association with **RANK**, **TIFA condensates**, and **viral LMP1 CTAR2** complexes • ADP-heptose studies show TRAF6 forms **cytosolic membraneless droplets/condensates** with dynamic exchange • Complex partners include **TAK1/TAB1/2, NEMO**, Ubc13/Uev1A, and receptor scaffolds (pqac-00000006, pqac-00000007, pqac-00000021, pqac-00000027) | Ayyasamy et al., 2024 — https://doi.org/10.1016/j.jbc.2024.107487 ; Giehler et al., 2024 — https://doi.org/10.1038/s41467-023-44455-w ; Li et al., 2024 — https://doi.org/10.34133/research.0315 |
| 2023-2024 mechanistic advances | • **2024 JBC:** 14-3-3ζ binds TRAF6, increases after RANKL, promotes **TRAF6 ubiquitination and proteasomal degradation**, weakens RANK–TRAF6 interaction, and suppresses osteoclastogenic signaling • **2024 Research:** TRAF6 undergoes **LLPS/condensation** in TIFA microreactors that enrich ubiquitin machinery and favor long **K63 polyUb** synthesis • **2024 Nat Commun:** EBV **LMP1 directly binds TRAF6** through a CTAR2 motif (**P379VQLSY**), with key interface residues defined biochemically/structurally • These studies move TRAF6 biology from linear pathway maps toward regulated **PPI interfaces, condensates, and degradative control** (pqac-00000014, pqac-00000015, pqac-00000020, pqac-00000021, pqac-00000028, pqac-00000029, pqac-00000032) | Ayyasamy et al., 2024 — https://doi.org/10.1016/j.jbc.2024.107487 ; Li et al., 2024 — https://doi.org/10.34133/research.0315 ; Giehler et al., 2024 — https://doi.org/10.1038/s41467-023-44455-w |
| Therapeutic targeting approaches | • **Small-molecule discovery:** virtual screening of **52,765 marine compounds** yielded candidate TRAF6 binders **CMNPD9212-16** and **CMNPD12791-8** with favorable in silico ADMET/MD profiles • **PPI targeting:** EBV study validated peptide disruption of **LMP1–TRAF6**; a RANK-derived inhibitor peptide blocked binding and reduced viability of EBV-transformed B cells • **Pathway modulation in bone disease:** recent work supports targeting **RANK–TRAF6** signaling or promoting TRAF6 degradation/stability control • No directly relevant TRAF6-targeted interventional clinical trials were retrieved in the tool search, so current implementation remains largely **preclinical** (pqac-00000005, pqac-00000030, pqac-00000032) | Wu et al., 2024 — https://doi.org/10.3390/md22060260 ; Giehler et al., 2024 — https://doi.org/10.1038/s41467-023-44455-w |
| Quantitative/statistical data | • Marine-drug screen: **52,765 compounds** screened; **405** docked; **6** advanced; **2** prioritized hits (CMNPD9212-16, CMNPD12791-8) (pqac-00000005) • TIFA/TRAF6 condensate study: ADP-LD-Hep produced about **6–7 puncta per cell**; NF-κB activation **IC50 ≈ 2.3 μM**; in vitro reconstitution used **TRAF6 20 μM, Ubc13 1 μM, Uev1A 1 μM, Ub 50 μM, E1 0.1 μM, ATP 2 mM** (pqac-00000020, pqac-00000021, pqac-00000026) • 14-3-3ζ study: proteasome inhibitors **MG132/lactacystin at 10 nM** blocked TRAF6 loss; RANKL stimulation increased 14-3-3ζ–TRAF6 interaction and osteoclast assays used **TRAP+ cells with ≥3 nuclei** as scoring criterion (pqac-00000013, pqac-00000015, pqac-00000017) • LMP1–TRAF6 study: RANK-derived inhibitor peptide blocked binding with **IC50 177 nM**; cell-penetrating peptide tested at **100 μM for 4 days** reduced LCL proliferation (pqac-00000030, pqac-00000032) | Wu et al., 2024 — https://doi.org/10.3390/md22060260 ; Li et al., 2024 — https://doi.org/10.34133/research.0315 ; Ayyasamy et al., 2024 — https://doi.org/10.1016/j.jbc.2024.107487 ; Giehler et al., 2024 — https://doi.org/10.1038/s41467-023-44455-w |


*Table: This table summarizes the most evidence-supported features of human TRAF6 (UniProt Q9Y4K3), including its domain architecture, E3 ligase activity, pathway roles, recent mechanistic advances, and preclinical targeting strategies. It is designed as a compact reference for functional annotation grounded only in the gathered evidence.*