Abstract

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 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.

Data availability

CryoEM maps and atomic coordinates for human IL-27 quaternary complex have been deposited in the EMDB (EMD- 26382) and PDB (7U7N) respectively.

The following data sets were generated

Article and author information

Author details

  1. Nathanael A Caveney

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  2. Caleb R Glassman

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  3. Kevin M Jude

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3675-5136
  4. Naotaka Tsutsumi

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3617-7145
  5. K Christopher Garcia

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    For correspondence
    kcgarcia@stanford.edu
    Competing interests
    K Christopher Garcia, is the founder of Synthekine..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9273-0278

Funding

Canadian Institutes of Health Research

  • Nathanael A Caveney

Howard Hughes Medical Institute

  • K Christopher Garcia

National Institute of Allergy and Infectious Diseases (R01-AI51321)

  • K Christopher Garcia

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrew C Kruse, Harvard Medical School, United States

Publication history

  1. Received: March 8, 2022
  2. Preprint posted: March 9, 2022 (view preprint)
  3. Accepted: May 16, 2022
  4. Accepted Manuscript published: May 17, 2022 (version 1)
  5. Version of Record published: May 27, 2022 (version 2)

Copyright

© 2022, Caveney et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nathanael A Caveney
  2. Caleb R Glassman
  3. Kevin M Jude
  4. Naotaka Tsutsumi
  5. K Christopher Garcia
(2022)
Structure of the IL-27 quaternary receptor signaling complex
eLife 11:e78463.
https://doi.org/10.7554/eLife.78463

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