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

Caini Liu; Shadi Swaidani; Wen Qian; Zizhen Kang; Paige Sun; Yue Han; Chenhui Wang; Muhammet Fatih Gulen; Weiguo Yin; Chunjiang Zhang; Paul L Fox; Mark Aronica; Thomas A Hamilton; Saurav Misra; Junpeng Deng; Xiaoxia Li

doi:10.1126/scisignal.2001843

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

Journal article

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

Caini Liu, Shadi Swaidani, Wen Qian, Zizhen Kang, Paige Sun, Yue Han, Chenhui Wang, Muhammet Fatih Gulen, Weiguo Yin, Chunjiang Zhang, …

Science signaling, Vol.4(197), pp.ra72-ra72

11/01/2011

DOI: 10.1126/scisignal.2001843

PMCID: PMC3282585

PMID: 22045852

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Abstract

Interleukin-17 (IL-17) and IL-25 signaling induce the expression of genes that encode inflammatory factors and they 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 IL-17 and IL-25 signaling, and it is recruited to their receptors through heterotypic interactions between their SEFIR [SEF (similar expression to fibroblast growth factor genes)/IL-17R] domains. Modeling of SEFIR domains has shown their structural similarity with the Toll-IL-1 receptor (TIR) domains of Toll-like receptors (TLRs) and the 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 IL-17R and IL-25R) did not affect Act1–IL-17RA interactions. Instead, deletion of the CC′ loop from Act1 or IL-17RA abolished the interaction between Act1 and IL-17RA, suggesting that SEFIR and TIR domains interact in different manners. Surface plasmon resonance measurements showed that a peptide corresponding to the CC′ loop bound directly to IL-17RA. A cell-permeable decoy peptide based on the CC′ loop sequence inhibited IL-17- and IL-25-mediated signaling, and it inhibited IL-17- and IL-25-induced responses in vitro and pulmonary inflammation in vivo. Together, these findings provide the molecular basis for the specificity of SEFIR versus 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 IL-17- and IL-25-asssociated inflammatory diseases.

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Title: Subtitle: A CC′ Loop Decoy Peptide Blocks the Interaction Between Act1 and IL-17RA to Attenuate IL-17- and IL-25-Induced Inflammation
Creators: Caini Liu - Cleveland Clinic
Shadi Swaidani - Cleveland Clinic
Wen Qian - Cleveland Clinic
Zizhen Kang - Cleveland Clinic
Paige Sun - Oklahoma State University
Yue Han - Oklahoma State University
Chenhui Wang - Cleveland Clinic
Muhammet Fatih Gulen - Cleveland Clinic
Weiguo Yin - Cleveland Clinic
Chunjiang Zhang - Cleveland Clinic
Paul L Fox - Cleveland Clinic
Mark Aronica - Cleveland Clinic
Thomas A Hamilton - Cleveland Clinic
Saurav Misra - Cleveland Clinic
Junpeng Deng - Oklahoma State University
Xiaoxia Li - Cleveland Clinic
Resource Type: Journal article
Publication Details: Science signaling, Vol.4(197), pp.ra72-ra72
DOI: 10.1126/scisignal.2001843
PMID: 22045852
PMCID: PMC3282585
NLM abbreviation: Sci Signal
ISSN: 1937-9145
eISSN: 1937-9145
Grant note: R01 GM080271-04 || GM / National Institute of General Medical Sciences : NIGMS R01 NS071996-02 || NS / National Institute of Neurological Disorders and Stroke : NINDS
Language: English
Date published: 11/01/2011
Academic Unit: Pathology; Iowa Neuroscience Institute
Record Identifier: 9984201251102771

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