Structure and signalling in the IL-17 receptor superfamily

The IL-17R complex is composed of IL-17RA and IL-17RC. Both subunits encode SEFIR domains , but a sequence similar to the TIR BB-loop is found only on IL-17RA, termed a TIR-like loop (TILL) . IL-17RA engages the SEFIR-containing ACT1 adaptor to mediate a variety of downstream events . Specifically, ACT1 is required for recruitment of TRAF6 (and possibly TRAF3), which is an essential upstream activator of the classical NF-κB pathway. It is not clear whether TRAF6 is also required for MAPK activation. Act1-/- cells fail to upregulate C/EBPβ (LAP and LAP* splice variants) and C/EBPδ as well, 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, 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/EBPβ on Thr-188 . A second functional domain on IL-17RA is located in the C-terminal region, and is not required for efficient activation of NF-κB or the MAPK pathways. However, deletion of this domain results in impaired alternative translation of C/EBPβ from 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/EBPβ on Thr-179, which is mediated by GSK3β . B. Comparison of IL-17R and TLR/IL-1R signalling. IL-17R and TLR/IL-1R signalling differ in functional receptor motifs (SEFIR/TILL versus TIR) and proximal adaptors (ACT1 versus MYD88 and TRIF), but converge on common pathways (NF-κB, C/EBP and MAPK). Hence these receptors activate similar, although not identical, panels of downstream genes.

Publication

Structure and signalling in the IL-17 receptor superfamily. () Sarah L. Gaffen. Nat Rev Immunol. ;9(8):556. Figure: F3. Homo sapiens

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