Figure 3.

Interleukin-17A signaling transduction pathway. In general, all IL-17R members contain a shared and conserved cytoplasmic motif named a SEFIR/SEFEX domain similar to the TIR region in IL-1 receptors and TLRs. Initially, IL-17R signaling triggers the recruitment of Act1, which includes a SEFIR domain and is required for IL-17R-Act1 combination. Subsequently, Act1 can ubiquitinate TRAF6 and E3 ubiquitin ligase. Upon ligand binding, TRAF2/5, TRAF4, and TRAF6 can be engaged by Act1 and stabilize mRNAs by activating RNA-binding proteins such as Arid5a, HuR, and DDX3X. IL-17A promotes the activities of AP1 and MAPK, as well as δ transcription factors and C/EBPβ activation (CBAD). IL-17A also accelerates IκBα degradation and IKK activation, thereby inducing NF-κB signaling. NF-κB in turn improves IL-17A-mediated proinflammatory and anti-microbial responses. IL-17A/NF-κB signal transduction can trigger a feedback loop that controls overactivation of the NF-κB cascade. TRAF, TNF-receptor associated factor; SEFIR, similar expression of fibroblast growth factor and IL-17Rs; SEFEX, SEFIR extension; TLRs, Toll-like receptors; C/EBPβ, CCAAT/enhancer-binding protein β; CBAD, C/EBPβ activation domain; AP1, activator protein 1; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; IKK, IκBα degradation and IκB kinase; JNK, Janus kinase; HuR, human antigen R.