IL-17-induced dimerization of IL-17RA drives the formation of the IL-17 signalosome to potentiate signaling

Cell Rep. 2022 Oct 18;41(3):111489. doi: 10.1016/j.celrep.2022.111489.

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.

Keywords: CP: Immunology; IL-17A; IL-17A/F; IL-17F; IL-17RA; IL-17RC; cytokine; signaling complex; signalosome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cytokines / metabolism
  • Dimerization
  • Humans
  • Interleukin-17* / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-1 / metabolism
  • Receptors, Interleukin-17* / genetics
  • Receptors, Interleukin-17* / metabolism

Substances

  • Receptors, Interleukin-17
  • Interleukin-17
  • Cytokines
  • RNA, Messenger
  • Receptors, Interleukin-1