Structure of the interleukin-5 receptor complex exemplifies the organizing principle of common beta cytokine signaling

Nathanael A Caveney; Grayson E Rodriguez; Christoph Pollmann; Thomas Meyer; Marta T Borowska; Steven C Wilson; Nan Wang; Xinyu Xiang; Karsten D Householder; Pingdong Tao; Leon L Su; Robert A Saxton; Jacob Piehler; K Christopher Garcia

doi:10.1016/j.molcel.2024.03.023

Structure of the interleukin-5 receptor complex exemplifies the organizing principle of common beta cytokine signaling

Mol Cell. 2024 Apr 5:S1097-2765(24)00268-5. doi: 10.1016/j.molcel.2024.03.023. Online ahead of print.

Authors

Affiliations

¹ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada. Electronic address: nathanael.caveney@ubc.ca.
² Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Department of Biology/Chemistry and Center for Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany.
⁴ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Biophysics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
⁷ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.

PMID: 38614096
DOI: 10.1016/j.molcel.2024.03.023

Abstract

Cytokines regulate immune responses by binding to cell surface receptors, including the common subunit beta (βc), which mediates signaling for GM-CSF, IL-3, and IL-5. Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear. We present the cryo-EM structure of the human IL-5 ternary receptor complex, revealing architectural principles for IL-5, GM-CSF, and IL-3. In mammalian cell culture, single-molecule imaging confirms hexameric IL-5 complex formation on cell surfaces. Engineered chimeric receptors show that IL-5 signaling, as well as IL-3 and GM-CSF, can occur through receptor heterodimerization, obviating the need for higher-order assemblies of βc dimers. These findings provide insights into IL-5 and βc receptor family signaling mechanisms, aiding in the development of therapies for diseases involving deranged βc signaling.

Keywords: GM-CSF; IL-3; IL-5; common beta; cytokines; signaling.