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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. Copyright © 2022 Novartis Pharma AG. Published by Elsevier Inc. All rights reserved.


Arnaud Goepfert, Carmen Barske, Sylvie Lehmann, Emmanuelle Wirth, Joschka Willemsen, Johann E Gudjonsson, Nicole L Ward, Mrinal K Sarkar, René Hemmig, Frank Kolbinger, Jean-Michel Rondeau. IL-17-induced dimerization of IL-17RA drives the formation of the IL-17 signalosome to potentiate signaling. Cell reports. 2022 Oct 18;41(3):111489

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PMID: 36260993

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