Research ArticleImmunology

A CC′ Loop Decoy Peptide Blocks the Interaction Between Act1 and IL-17RA to Attenuate IL-17– and IL-25–Induced Inflammation

Sci. Signal.  01 Nov 2011:
Vol. 4, Issue 197, pp. ra72
DOI: 10.1126/scisignal.2001843

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Interleukin-17 (IL-17) and IL-25 signaling induce the expression of genes encoding inflammatory factors and are implicated in the pathology of various inflammatory diseases. Nuclear factor κB (NF-κB) activator 1 (Act1) is an adaptor protein and E3 ubiquitin ligase that is critical for signaling by either IL-17 or IL-25, and it is recruited to their receptors (IL-17R and IL-25R) through heterotypic interactions between the SEFIR [SEF (similar expression to fibroblast growth factor genes) and IL-17R] domain of Act1 and that of the receptor. SEFIR domains have structural similarity with the Toll–IL-1 receptor (TIR) domains of Toll-like receptors and IL-1R. Whereas the BB′ loop of TIR is required for TIR-TIR interactions, we found that deletion of the BB′ loop from Act1 or IL-17RA (a common subunit of both IL-17R and IL-25R) did not affect Act1–IL-17RA interactions; rather, deletion of the CC′ loop from Act1 or IL-17RA abolished the interaction between both proteins. Surface plasmon resonance measurements showed that a peptide corresponding to the CC′ loop of Act1 bound directly to IL-17RA. A cell-permeable decoy peptide based on the CC′ loop sequence inhibited IL-17– or IL-25–mediated signaling in vitro, as well as IL-17– and IL-25–induced pulmonary inflammation in mice. Together, these findings provide the molecular basis for the specificity of SEFIR-SEFIR versus TIR-TIR domain interactions and consequent signaling. Moreover, we suggest that the CC′ loop motif of SEFIR domains is a promising target for therapeutic strategies against inflammatory diseases associated with IL-17 or IL-25 signaling.

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