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Sci. Signal., 1 November 2011
Vol. 4, Issue 197, p. ra72
[DOI: 10.1126/scisignal.2001843]

RESEARCH ARTICLES

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

Caini Liu1*, Shadi Swaidani1*, Wen Qian1, Zizhen Kang1, Paige Sun2, Yue Han2, Chenhui Wang1, Muhammet Fatih Gulen1, Weiguo Yin1, Chunjiang Zhang1, Paul L. Fox3, Mark Aronica4, Thomas A. Hamilton1, Saurav Misra5, Junpeng Deng2, and Xiaoxia Li1{dagger}

1 Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
2 Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA.
3 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
4 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
5 Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

* These authors contributed equally to this work.

Abstract: 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 {kappa}B (NF-{kappa}B) 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.

{dagger} To whom correspondence should be addressed. E-mail: lix{at}ccf.org

Citation: C. Liu, S. Swaidani, W. Qian, Z. Kang, P. Sun, Y. Han, C. Wang, M. F. Gulen, W. Yin, C. Zhang, P. L. Fox, M. Aronica, T. A. Hamilton, S. Misra, J. Deng, X. Li, A CC' Loop Decoy Peptide Blocks the Interaction Between Act1 and IL-17RA to Attenuate IL-17– and IL-25–Induced Inflammation. Sci. Signal. 4, ra72 (2011).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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