Structure of the IL-27 quaternary receptor signaling complex

• DOI: 10.7554/elife.78463
• Publication Date: 2022-05-17T12:00:34Z
• Authors: Nathanael A Caveney; Caleb R Glassman; Kevin M Jude; Naotaka Tsutsumi; K Christopher Garcia
• Keywords: Interleukin-27; 0303 health sciences; QH301-705.5; Science; Q; R; receptors; Receptors, Interleukin; Interleukin-12; 03 medical and health sciences; Immunology and Inflammation; cytokine; Cytokine Receptor gp130; Medicine; Humans; Biology (General); signaling; Protein Structure, Quaternary

Interleukin 27 (IL-27) is a heterodimeric cytokine that functions to constrain T cell-mediated inflammation and plays an important role in immune homeostasis. Binding of IL-27 to cell surface receptors, IL-27Rα and gp130, results in activation of receptor-associated Janus Kinases and nuclear translocation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT3 transcription factors. Despite the emerging therapeutic importance of this cytokine axis in cancer and autoimmunity, a molecular blueprint of the IL-27 receptor signaling complex, and its relation to other gp130/IL-12 family cytokines, is currently unclear. We used cryogenic-electron microscopy to determine the quaternary structure of IL-27, composed of p28 and Epstein-Barr Virus-Induced 3 (Ebi3) subunits, bound to receptors, IL-27Rα and gp130. The resulting 3.47 Å resolution structure revealed a three-site assembly mechanism nucleated by the central p28 subunit of the cytokine. The overall topology and molecular details of this binding are reminiscent of IL-6 but distinct from related heterodimeric cytokines IL-12 and IL-23. These results indicate distinct receptor assembly mechanisms used by heterodimeric cytokines with important consequences for targeted agonism and antagonism of IL-27 signaling.