Structural transitions enable interleukin-18 maturation and signaling.

IL-18 NMR caspase-1 conformational change cryo-EM cytokine cleavage inflammatory activity pro-IL-18

Journal

Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918

Informations de publication

Date de publication:
08 May 2024
Historique:
received: 26 10 2023
revised: 28 02 2024
accepted: 17 04 2024
medline: 12 5 2024
pubmed: 12 5 2024
entrez: 11 5 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.immuni.2024.04.015 PMID: 38733997
pubmed: 38733997
pii: S1074-7613(24)00220-6
doi: 10.1016/j.immuni.2024.04.015
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests J.C.K. consults and holds equity in Corner Therapeutics, Larkspur Biosciences, and Neumora Therapeutics. H.W. is a co-founder and chair of the scientific advisory board of Ventus Therapeutics. None of these relationships influenced this study.

Auteurs

Ying Dong (Y)

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.

Jeffrey P Bonin (JP)

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.

Pascal Devant (P)

Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Zhuoyi Liang (Z)

Bioscience and Biomedical Engineering Thrust, Brain and Intelligence Research Institute, The Hong Kong University of Science and Technology (Guangzhou), Guangzhou, China.

Alexander I M Sever (AIM)

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.

Julian Mintseris (J)

Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA, USA.

James M Aramini (JM)

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.

Gang Du (G)

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.

Stephen P Gygi (SP)

Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA, USA.

Jonathan C Kagan (JC)

Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: jonathan.kagan@childrens.harvard.edu.

Lewis E Kay (LE)

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.

Hao Wu (H)

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.

Classifications MeSH