A CC' loop decoy peptide blocks the interaction between Act1 and IL-17RA to attenuate IL-17- and IL-25-induced inflammation.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Blotting, Western, Cells, Cultured, Female, HEK293 Cells, HeLa Cells, Humans, Interleukin-17, Interleukins, Mice, Mice, Inbred BALB C, Models, Molecular, Molecular Sequence Data, Mutation, Peptides, Pneumonia, Protein Binding, Protein Structure, Tertiary, Receptors, Interleukin-17, Signal Transduction, Surface Plasmon Resonance
Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Blotting, Western, Cells, Cultured, Female, HEK293 Cells, HeLa Cells, Humans, Interleukin-17, Interleukins, Mice, Mice, Inbred BALB C, Models, Molecular, Molecular Sequence Data, Mutation, Peptides, Pneumonia, Protein Binding, Protein Structure, Tertiary, Receptors, Interleukin-17, Signal Transduction, Surface Plasmon Resonance
Sci Signal
Date: Nov. 03, 2011
PubMed ID: 22045852
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