Structural transitions enable interleukin-18 maturation and signaling

Ying Dong; Jeffrey P Bonin; Pascal Devant; Zhuoyi Liang; Alexander I M Sever; Julian Mintseris; James M Aramini; Gang Du; Stephen P Gygi; Jonathan C Kagan; Lewis E Kay; Hao Wu

doi:10.1016/j.immuni.2024.04.015

Structural transitions enable interleukin-18 maturation and signaling

Immunity. 2024 Jul 9;57(7):1533-1548.e10. doi: 10.1016/j.immuni.2024.04.015. Epub 2024 May 10.

Authors

Affiliations

¹ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
² Departments of Molecular Genetics and Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada; Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
³ Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Bioscience and Biomedical Engineering Thrust, Brain and Intelligence Research Institute, The Hong Kong University of Science and Technology (Guangzhou), Guangzhou, China.
⁵ Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada; Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
⁶ Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA, USA.
⁷ Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.
⁸ Departments of Molecular Genetics and Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada; Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada. Electronic address: lewis.kay@utoronto.ca.
⁹ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. Electronic address: wu@crystal.harvard.edu.

PMID: 38733997
PMCID: PMC11236505 (available on 2025-07-09)
DOI: 10.1016/j.immuni.2024.04.015

Abstract

Several interleukin-1 (IL-1) family members, including IL-1β and IL-18, require processing by inflammasome-associated caspases to unleash their activities. Here, we unveil, by cryoelectron microscopy (cryo-EM), two major conformations of the complex between caspase-1 and pro-IL-18. One conformation is similar to the complex of caspase-4 and pro-IL-18, with interactions at both the active site and an exosite (closed conformation), and the other only contains interactions at the active site (open conformation). Thus, pro-IL-18 recruitment and processing by caspase-1 is less dependent on the exosite than the active site, unlike caspase-4. Structure determination by nuclear magnetic resonance uncovers a compact fold of apo pro-IL-18, which is similar to caspase-1-bound pro-IL-18 but distinct from cleaved IL-18. Binding sites for IL-18 receptor and IL-18 binding protein are only formed upon conformational changes after pro-IL-18 cleavage. These studies show how pro-IL-18 is selected as a caspase-1 substrate, and why cleavage is necessary for its inflammatory activity.

Keywords: IL-18; NMR; caspase-1; conformational change; cryo-EM; cytokine cleavage; inflammatory activity; pro-IL-18.

MeSH terms

Animals
Binding Sites
Caspase 1* / metabolism
Cryoelectron Microscopy*
Humans
Inflammasomes / metabolism
Intercellular Signaling Peptides and Proteins
Interleukin-18* / metabolism
Mice
Models, Molecular
Protein Binding
Protein Conformation
Receptors, Interleukin-18 / metabolism
Signal Transduction*

Substances

Interleukin-18
Caspase 1
Inflammasomes
interleukin-18 binding protein
Receptors, Interleukin-18
Intercellular Signaling Peptides and Proteins

Abstract

MeSH terms

Substances

Grants and funding