| TRAF5 is a TNF receptor–associated factor family adaptor that assembles signaling complexes downstream of several TNF receptor superfamily members, where it contributes to activation and tuning of NF‑κB and MAPK pathways in lymphoid and myeloid cells. The protein contains an N‑terminal RING‑like zinc finger and coiled‑coil region that support oligomerization and E3‑ligase–associated functions, and a C‑terminal TRAF domain composed of a TRAF‑N coiled‑coil and TRAF‑C β‑sandwich that mediates trimerization and receptor or adaptor binding, allowing TRAF5 trimers to dock onto cytoplasmic tails of co‑stimulatory TNFR family receptors such as CD27, CD30, CD40, 4‑1BB, and GITR. Engagement of these receptors recruits TRAF5, often together with TRAF2, into membrane‑proximal complexes where TRAF5 associates with upstream adaptors and ubiquitin ligases and helps assemble Lys‑63–linked polyubiquitin scaffolds that promote recruitment and activation of TAK1 and the IKK complex, leading to phosphorylation and degradation of IκB and nuclear translocation of NF‑κB, as well as activation of JNK and p38 MAPKs. TRAF5 is also an effector in IL‑17A signaling, where it binds the adaptor Act1 and modulates IL‑17 receptor–associated complexes, and biochemical analyses show that Lys‑63–linked polyubiquitination of TRAF5 is required for optimal IL‑17–induced NF‑κB activation and expression of RORγt‑dependent inflammatory genes, including those implicated in Th17‑driven autoimmunity. TRAF5 functions as a positive regulator in lymphocyte costimulatory signaling, as evidenced by mice lacking Traf5 exhibiting impaired intracellular signaling and reduced proliferation or survival following co-stimulation through receptors such as CD27, CD30, and 4-1BB, which act in concert with antigen receptor pathways to modulate B- and T-cell responses. TRAF5 polymorphisms increase susceptibility to rheumatoid arthritis and other autoimmune diseases. Changes in TRAF5 function, particularly in synovial fibroblasts and Th17 cells, alter the production of cytokines such as IL-6, integrating TRAF5 into the molecular network that regulates chronic joint inflammation and autoimmune pathology. |
