Journal
IMMUNITY
Volume 48, Issue 1, Pages 45-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2017.12.008
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Funding
- Flanders Agency for Innovation and Entrepreneurship (VLAIO-Flanders, Belgium)
- Research Foundation Flanders (FWO, Belgium)
- Ghent University Hospital Spearhead Initiative for Immunology Research
- Jeffrey Modell Foundation
- NIAMS/NIH [AR62173]
- National Psoriasis Foundation Translational Research Grant
- Research Foundation Flanders (FWO grant) [G0C2214N]
- Hercules Foundation [AUGE-11-029]
- VIB
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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-12Rb1 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.
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