Goepfert, Arnaud, Barske, Carmen, Lehmann, Sylvie, Wirth, Emmanuelle, Willemsen, Joschka, Gudjonsson, Johann, Ward, Nicole, Sarkar, Mrinal, Hemmig, Rene, Kolbinger, Frank and Rondeau, Jean-Michel (2022) IL-17-induced dimerization of IL-17RA drives the formation of the IL-17 signalosome to potentiate signaling. Cell reports, 41 (3). p. 111489. ISSN 2211-1247

Abstract

Signaling through innate immune receptors such as the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) superfamily proceeds via the assembly of large membrane-proximal complexes or "signalosomes." Although structurally distinct, the IL-17 receptor family triggers cellular responses that are typical of innate immune receptors. The IL-17RA receptor subunit is shared by several members of the IL-17 family. Using a combination of crystallographic, biophysical, and mutational studies, we show that IL-17A, IL-17F, and IL-17A/F induce IL-17RA dimerization. X-ray analysis of the heteromeric IL-17A complex with the extracellular domains of the IL-17RA and IL-17RC receptors reveals that cytokine-induced IL-17RA dimerization leads to the formation of a 2:2:2 hexameric signaling assembly. Furthermore, we demonstrate that the formation of the IL-17 signalosome potentiates IL-17-induced IL-36γ and CXCL1 mRNA expression in human keratinocytes, compared with a dimerization-defective IL-17RA variant.

Item Type:	Article
Date Deposited:	03 Nov 2022 00:45
Last Modified:	03 Nov 2022 00:45
URI:	https://oak.novartis.com/id/eprint/46992