FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation
- 4 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 21 (7), 736-745
- https://doi.org/10.1038/s41590-020-0669-6
Abstract
Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1β) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1β and GSDMD processing, but abrogates pore formation, thereby preventing IL-1β release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.Keywords
This publication has 42 references indexed in Scilit:
- Inflammasomes and Their Roles in Health and DiseaseAnnual Review of Cell and Developmental Biology, 2012
- Nonprofit drugs as the salvation of the world's healthcare systems: the case of Antabuse (disulfiram)Drug Discovery Today, 2012
- Regulation of inflammasome signalingNature Immunology, 2012
- Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 KinaseCell, 2012
- Anti-inflammatory Compounds Parthenolide and Bay 11-7082 Are Direct Inhibitors of the InflammasomeJournal of Biological Chemistry, 2010
- Prediction of reversibly oxidized protein cysteine thiols using protein structure propertiesProtein Science, 2008
- Familial cold autoinflammatory syndrome: Phenotype and genotype of an autosomal dominant periodic feverJournal of Allergy and Clinical Immunology, 2001
- A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening AssaysSLAS Discovery, 1999
- Disulfiram Is a Potent Inhibitor of Proteases of the Caspase FamilyChemical Research in Toxicology, 1997
- The pharmacology and toxicology of disulfiram and its metabolitesActa Psychiatrica Scandinavica, 1992