PT  - JOURNAL ARTICLE
AU  - Liu, Caini
AU  - Swaidani, Shadi
AU  - Qian, Wen
AU  - Kang, Zizhen
AU  - Sun, Paige
AU  - Han, Yue
AU  - Wang, Chenhui
AU  - Gulen, Muhammet Fatih
AU  - Yin, Weiguo
AU  - Zhang, Chunjiang
AU  - Fox, Paul L.
AU  - Aronica, Mark
AU  - Hamilton, Thomas A.
AU  - Misra, Saurav
AU  - Deng, Junpeng
AU  - Li, Xiaoxia
TI  - A CC′ Loop Decoy Peptide Blocks the Interaction Between Act1 and IL-17RA to Attenuate IL-17– and IL-25–Induced Inflammation
AID  - 10.1126/scisignal.2001843
DP  - 2011 Nov 01
TA  - Science Signaling
PG  - ra72--ra72
VI  - 4
IP  - 197
4099  - http://stke.sciencemag.org/content/4/197/ra72.short
4100  - http://stke.sciencemag.org/content/4/197/ra72.full
SO  - Sci. Signal.2011 Nov 01; 4
AB  - 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.