Defining functional motifs within interleukin-17 receptor cytoplasmic tail
MetadataShow full item record
Interleukin-17 and its receptors are members of a proinflammatory cytokine family. The IL-17 receptor complex (composed of two subunits, IL-17RA and IL-17RC) is ubiquitously expressed, and cytoplasmic tails of the subunits contain functional domains similar to those of Toll-Like Receptor (TLR) family. These functional domains of IL-17RA are termed SEFIR and TILL, and it has been shown that these play a major role in activating intracellular signaling cascades, leading to inflammation, host defense and/or autoimmunity. IL-17RC does not possess an obvious TILL domain, although it is required for receptor signaling. The aims of this study were to examine functional and biological characteristics of the IL-17 receptor cytoplasmic TILL domain in three ways: (1) to test the importance of the conserved amino acid residues from TLR/IL-1R, (2) to map a boundary of the TILL domain, and (3) to determine functionality of IL-17RA/RC chimeric receptor. Functions and molecular biology of IL-17RA and IL-17RC were assessed by transfection of IL-17RA-deficient fibroblasts with various mutants and a chimeric receptor construct composed of the IL-17RA extracellular domain and the IL-17RC intracellular domain. ELISA data showed that mutations E533A and R549A do not significantly affect IL-17 signaling, suggesting that the putative salt bridge in the TILL domain does not form. Deletion of IL-17RA to residue 585 was not functional whereas a deletion to 665 is, demonstrating that the minimal functional domain lies between residues 585 and 665. Furthermore, the IL-17RA/RC chimera was not functional, indicating that the IL-17RA cytoplasmic tail could not be replaced with IL-17RC.