Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1

Immunity. 2018 Jan 16;48(1):45-58.e6. doi: 10.1016/j.immuni.2017.12.008. Epub 2017 Dec 26.

Abstract

Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.

Keywords: Crohn’s disease; IL-12Rβ1; IL-23; IL-23 receptor; cytokine-receptor complex; inflammation; inflammatory bowel disease; psoriasis; rheumatoid arthritis; structure.

Publication types

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

MeSH terms

  • Animals
  • Calorimetry / methods
  • Cell Line
  • Humans
  • Interferometry / methods
  • Interleukin-12 Receptor beta 1 Subunit / metabolism*
  • Interleukin-12 Subunit p40 / metabolism
  • Interleukin-23 / metabolism*
  • Male
  • Mice
  • Protein Binding / physiology
  • Real-Time Polymerase Chain Reaction
  • Receptors, Interleukin / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • IL12B protein, human
  • IL23R protein, human
  • Interleukin-12 Receptor beta 1 Subunit
  • Interleukin-12 Subunit p40
  • Interleukin-23
  • Receptors, Interleukin