士锋生物：白介素17诱导的信号通路图

Schematic depicting interleukin-17 receptor （IL-17R） signalling. The IL-17R complex is composed of IL-17RA and IL-17RC. Both subunits encode SEF/IL-17R （SEFIR） domains, but a sequence similar to the Toll/IL-1R （TIR） BB-loop is found only in IL-17RA, termed a TIR-like loop （TILL）. IL-17RA engages the SEFIR domain-containing adaptor ACT1 to mediate various downstream events. Specifically, ACT1 is required for recruitment of TNFR-associated factor 6 （TRAF6） and possibly TRAF3, which are essential upstream activators of the canonical nuclear factor-κB （NF-κB） pathway. It is not clear whether TRAF6 is also required for the activation of the mitogen-activated protein kinase （MAPK） p38. Act1-/- cells fail to upregulate the expression of the liver-enriched activator protein （LAP） and LAP* splice variants of CCAAT/enhancer-binding protein-β（C/EBPβ） or the expression of C/EBPδ, another event that might be downstream of NF-κB. ACT1, but not TRAF6, is required for IL-17A-induced stabilization of several target mRNAs, particularly those encoding chemokines and cytokines. Interestingly, extracellular signal-regulated kinase （ERK） might also be controlled, at least indirectly, by ACT1-independent pathways, as Act1-/- cells show strong upregulation of ERK phosphorylation 24 hours after IL-17A stimulation. ERK mediates rapid phosphorylation of C/EBPβon threonine 188 . A second functional domain on IL-17RA is located in the carboxy-terminal region and is not required for efficient activation of NF-κB and MAPK pathways. However, deletion of this domain results in impaired alternative translation of C/EBPβfrom the LAP isoform to the LAP* isoform, and hence was termed the C/EBPβ-activation domain （CBAD）. The CBAD is also required for IL-17A-mediated inducible phosphorylation of C/EBPβon threonine 179, which is mediated by glycogen synthase kinase 3β（GSK3β）. b | Comparison of IL-17R and Toll-like receptor （TLR） signalling. IL-17R and TLR （or IL-1R, not shown） signalling pathways use different functional receptor motifs （SEFIR and TILL versus Toll/IL-1R （TIR） domains） and proximal adaptors （ACT1 versus MYD88 （myeloid differentiation primary-response protein 88） and TRIF （TIR-domain-containing adaptor protein inducing IFNβ））, but converge on common pathways （NF-κB, C/EBP and MAPKs）. Therefore, these receptors activate similar, although not identical, panels of downstream genes. IκBξ, inhibitor of NF-κB-ξ; IRF3, interferon regulatory factor 3; P13K, phosphoinositide 3-kinase.

IL 17 Signaling Pathway

IL-17R家族的配体 - 受体关系和主要结构特点IL-17R family ligand–receptor relationships and main structural features