TY - JOUR
T1 - Structure of the IL-27 quaternary receptor signaling complex
AU - Caveney, Nathanael A.
AU - Glassman, Caleb R.
AU - Jude, Kevin M.
AU - Tsutsum, Naotaka
AU - Garcia, K. Christopher
N1 - Funding Information:
We thank Rui Yan at the HHMI Janelia CryoEM Facility for help in microscope operation and final data collection. We thank Liz Montabana and Stanford cEMc for microscope access for preliminary data collection. NAC is a CIHR postdoctoral fellow. KCG is an investigator with the Howard Hughes Medical Institute. KCG is supported by National Institutes of Health grant R01-AI51321, the Mathers Foundation, and the Ludwig Foundation.
Publisher Copyright:
© Caveney, Glassman et al.
PY - 2022/5
Y1 - 2022/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85131108585&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85131108585&partnerID=8YFLogxK
U2 - 10.7554/eLife.78463
DO - 10.7554/eLife.78463
M3 - Article
C2 - 35579417
AN - SCOPUS:85131108585
SN - 2050-084X
VL - 11
JO - eLife
JF - eLife
M1 - e78463
ER -
