title: IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail.
abstract: 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.
authors.affiliation: Department of Oral Biology, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
authors.forename: Allen W
authors.initials: AW
authors.lastname: Ho
authors.forename: Fang
authors.initials: F
authors.lastname: Shen
authors.forename: Heather R
authors.initials: HR
authors.lastname: Conti
authors.forename: Nayan
authors.initials: N
authors.lastname: Patel
authors.forename: Erin E
authors.initials: EE
authors.lastname: Childs
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Peterson
authors.forename: Nydiaris
authors.initials: N
authors.lastname: Hernández-Santos
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002180:Candidiasis, Oral / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009960:Oropharynx / Q000276:immunology / Q000382:microbiology; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014162:Transfection
chemical_list: D020381:Interleukin-17; D020033:Protein Isoforms; D053722:Receptors, Interleukin-17