TRAF3-interacting protein 2 (TRAF3IP2) (CIKS)

CIKS, also known as TRAF3-interacting protein 2 (TRAF3IP2) or ACT1, is a pivotal intracellular adaptor protein and E3 ubiquitin ligase that serves as a central node in the interleukin-17 (IL-17) signaling pathway (1, 2, 8). It is essential for the activation of NF-kappaB and JNK/AP-1 signaling cascades, which are critical for the induction of inflammatory and immune responses in various cell types, including keratinocytes and fibroblasts (2, 9, 44). Genetic variants in the TRAF3IP2 gene, particularly the rs33980500 (D10N) polymorphism, are strongly associated with susceptibility to chronic inflammatory conditions such as psoriasis and psoriatic arthritis (5, 10, 29). Beyond its role in autoimmunity, CIKS has been identified as a driver of progression in aggressive malignancies like triple-negative breast cancer and glioblastoma, where it promotes tumor growth, angiogenesis, and metabolic reprogramming (27, 31, 48). While current clinical therapies primarily target the IL-17 cytokine or its receptor, CIKS is an emerging therapeutic target for small molecule inhibitors and gene-silencing strategies aimed at disrupting the inflammatory feed-forward loop in autoimmune diseases and treatment-resistant cancers (3, 23, 31, 49).

Other names

ACT1NF-kappa-B activator 1Connection to IKK and SAPK/JNKC6orf2C6orf4C6orf5C6orf6CANDF8PSORS13

CIKS (TRAF3IP2/ACT1) acts as an essential adaptor protein in the IL-17 signaling pathway. It contains a SEFIR domain that mediates its interaction with the IL-17 receptor (IL-17R) and an N-terminal domain that recruits TRAF6. This recruitment, facilitated by the E3 ubiquitin ligase activity of CIKS, leads to the activation of the IKK complex and subsequent NF-kappaB translocation, as well as the activation of MAPK/JNK pathways. These cascades drive the expression of pro-inflammatory cytokines, chemokines, and antimicrobial peptides.