IL-17RC Is Required for Immune Signaling via an Extended SEF/IL-17R Signaling Domain in the Cytoplasmic Tail

作者：Allen W. Ho, Fang Shen, Heather R. Conti, Nayan M Patel, Erin E. Childs, Alanna Peterson, Nydiaris Hernández‐Santos, Jay K. Kolls, Larry Kane, Wenjun Ouyang, Sarah L. Gaffen · 发表于：The Journal of Immunology · 年份：2010 · DOI：10.4049/jimmunol.0903739 · 被引用次数：127 · 研究领域：Psoriasis: Treatment and Pathogenesis、Immunodeficiency and Autoimmune Disorders、Whipple's Disease and Interleukins

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-depend...