IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail.
IL-17 mediates essential inflammatory responses in host defense and autoimmunity. The IL-17A-IL-17F signaling complex is composed of IL-17RA and IL-17RC, both of which are necessary for signal transduction. To date, the specific contribution of IL-17RC to downstream signaling remains poorly understood. To define the regions within the IL-17RC cytoplasmic tail ... required for signal transduction, we assayed signaling by a panel of IL-17RC deletion mutants. These findings reveal that IL-17RC inducibly associates with a specific glycosylated IL-17RA isoform, in a manner independent of the IL-17RC cytoplasmic tail. Using expression of the IL-17 target genes IL-6 and 24p3/lipocalin-2 as a readout, functional reconstitution of signaling in IL-17RC(-/-) fibroblasts required the SEF/IL-17R signaling domain (SEFIR), a conserved motif common to IL-17R family members. Unexpectedly, the IL-17RC SEFIR alone was not sufficient to reconstitute IL-17-dependent signaling. Rather, an additional sequence downstream of the SEFIR was also necessary. We further found that IL-17RC interacts directly with the adaptor/E3 ubiquitin ligase Act1, and that the functional IL-17RC isoforms containing the extended SEFIR region interact specifically with a phosphorylated isoform of Act1. Finally, we show that IL-17RC is required for in vivo IL-17-dependent responses during oral mucosal infections caused by the human commensal fungus Candida albicans. These results indicate that IL-17RC is vital for IL-17-dependent signaling both in vitro and in vivo. Insight into the mechanisms by which IL-17RC signals helps shed light on IL-17-dependent inflammatory responses and may ultimately provide an avenue for therapeutic intervention in IL-17-mediated diseases.
Mesh Terms:
Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Blotting, Western, Candidiasis, Oral, Cell Line, Cells, Cultured, Disease Models, Animal, Fibroblasts, Flow Cytometry, Genetic Predisposition to Disease, Humans, Interleukin-17, Mice, Mice, Knockout, Mutation, Oropharynx, Protein Binding, Protein Isoforms, Receptors, Interleukin-17, Signal Transduction, Transfection
Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Blotting, Western, Candidiasis, Oral, Cell Line, Cells, Cultured, Disease Models, Animal, Fibroblasts, Flow Cytometry, Genetic Predisposition to Disease, Humans, Interleukin-17, Mice, Mice, Knockout, Mutation, Oropharynx, Protein Binding, Protein Isoforms, Receptors, Interleukin-17, Signal Transduction, Transfection
J. Immunol.
Date: Jul. 15, 2010
PubMed ID: 20554964
View in: Pubmed Google Scholar
Download Curated Data For This Publication
138661
Switch View:
- Interactions 2