title: A CC' loop decoy peptide blocks the interaction between Act1 and IL-17RA to attenuate IL-17- and IL-25-induced inflammation.
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 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.
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors: Caini
authors: C
authors: Liu
authors: Shadi
authors: S
authors: Swaidani
authors: Wen
authors: W
authors: Qian
authors: Zizhen
authors: Z
authors: Kang
authors: Paige
authors: P
authors: Sun
authors: Yue
authors: Y
authors: Han
authors: Chenhui
authors: C
authors: Wang
authors: Muhammet Fatih
authors: MF
authors: Gulen
authors: Weiguo
authors: W
authors: Yin
authors: Chunjiang
authors: C
authors: Zhang
authors: Paul L
authors: PL
authors: Fox
authors: Mark
authors: M
authors: Aronica
authors: Thomas A
authors: TA
authors: Hamilton
authors: Saurav
authors: S
authors: Misra
authors: Junpeng
authors: J
authors: Deng
authors: Xiaoxia
authors: X
authors: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020381:Interleukin-17 / Q000633:toxicity; D007378:Interleukins / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D053722:Receptors, Interleukin-17 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020349:Surface Plasmon Resonance
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D007378:Interleukins; C442281:Mydgf protein, mouse; D010455:Peptides; D053722:Receptors, Interleukin-17; C515963:Traf3ip2 protein, mouse