Cytokine Growth Factor Rev. 2026 Aug 18;91:139-149. doi: 10.1016/j.cytogfr.2026.08.003. Online ahead of print.
ABSTRACT
Interleukin-17 (IL-17) family cytokines drive protective mucocutaneous immunity and, when dysregulated, a broad spectrum of inflammatory and autoimmune disease; almost all IL-17 receptor signaling converges on a single cytoplasmic adaptor, TRAF3IP2 (Act1/CIKS). This 574-amino-acid protein and U-box E3 ubiquitin ligase couples the IL-17 receptor to NF-κB and mitogen-activated protein kinase activation and also integrates non-IL-17 inputs through TRAF6, TRAF2/TRAF5, and TRAF3. Human germline variation in TRAF3IP2 offers a natural dissection of this adaptor along its signaling modules. Common coding variants that weaken TRAF6 recruitment, mainly rs33980500 (p.Asp19Asn), increase susceptibility to psoriasis and psoriatic arthritis, whereas rare biallelic variants that abolish SEFIR-mediated IL-17 receptor coupling cause chronic mucocutaneous candidiasis; an intermediate SEFIR lesion produces discoid lupus erythematosus. Additional associations span systemic lupus erythematosus, inflammatory bowel disease, cardiovascular disease, and malignancy. Interpreting these alleles has been limited by the absence of a variant catalogue anchored to a single protein reference and by a +9-residue offset between the 574- and 565-amino-acid isoforms that has propagated numbering errors across the literature. Here we assemble a reference-aligned atlas of 17 functionally or clinically annotated TRAF3IP2 variants on the 574-amino-acid sequence (NP_671733.2) and map each to the signaling interaction it perturbs. The resulting domain-to-phenotype framework, advanced as hypothesis-generating rather than deterministic, organizes variant effects along the IL-17 signaling axis, distinguishing TRAF-recruitment perturbation from receptor-coupling failure, and identifies the adaptor surfaces whose selective pharmacologic disruption could attenuate IL-17-driven inflammation in cardiovascular and oncologic disease while sparing antifungal immunity.
PMID:42632295 | DOI:10.1016/j.cytogfr.2026.08.003