2. Academic Validation
  3. Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1

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.
Yehudi Bloch 1,  Laura Bouchareychas 2,  Romain Merceron 1,  Katarzyna Składanowska 1,  Lien Van den Bossche 3,  Sammy Detry 1,  Srinath Govindarajan 4,  Dirk Elewaut 4,  Filomeen Haerynck 5,  Melissa Dullaers 6,  Iannis E Adamopoulos 2,  Savvas N Savvides 7
Affiliations

Affiliations

  • 1 Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium; VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium.
  • 2 Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, CA 95817, USA.
  • 3 Clinical Immunology Research Lab, Department of Pulmonary Medicine, Ghent University Hospital, 9000 Ghent, Belgium; Center for Primary Immunodeficiency, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, 9000 Ghent, Belgium.
  • 4 VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium; Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, 9000 Ghent, Belgium.
  • 5 Clinical Immunology Research Lab, Department of Pulmonary Medicine, Ghent University Hospital, 9000 Ghent, Belgium; Center for Primary Immunodeficiency, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, 9000 Ghent, Belgium; Department of Pediatrics, Division of Pediatric Immunology and Pulmonology, Ghent University Hospital, 9000 Ghent, Belgium.
  • 6 Clinical Immunology Research Lab, Department of Pulmonary Medicine, Ghent University Hospital, 9000 Ghent, Belgium; Center for Primary Immunodeficiency, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, 9000 Ghent, Belgium; Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, 9000 Ghent, Belgium.
  • 7 Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium; VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium. Electronic address: [email protected].
PMID: 29287995 DOI: 10.1016/j.immuni.2017.12.008
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.

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