Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion
Top Cited Papers
Open Access
- 27 November 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Research
- Vol. 25 (12), 1285-1298
- https://doi.org/10.1038/cr.2015.139
Abstract
Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1β in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1β secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd−/− cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd−/− cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.Keywords
This publication has 27 references indexed in Scilit:
- Group-DIA: analyzing multiple data-independent acquisition mass spectrometry data filesNature Methods, 2015
- Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell deathNature, 2015
- Caspase-11 cleaves gasdermin D for non-canonical inflammasome signallingNature, 2015
- Inflammatory caspases are innate immune receptors for intracellular LPSNature, 2014
- Mechanisms and Functions of InflammasomesCell, 2014
- Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formationNature Communications, 2014
- Investigation of Receptor interacting protein (RIP3)-dependent Protein Phosphorylation by Quantitative PhosphoproteomicsMolecular & Cellular Proteomics, 2012
- Targeted Data Extraction of the MS/MS Spectra Generated by Data-independent Acquisition: A New Concept for Consistent and Accurate Proteome AnalysisMolecular & Cellular Proteomics, 2012
- iProphet: Multi-level Integrative Analysis of Shotgun Proteomic Data Improves Peptide and Protein Identification Rates and Error EstimatesMolecular & Cellular Proteomics, 2011
- ASC, a Novel 22-kDa Protein, Aggregates during Apoptosis of Human Promyelocytic Leukemia HL-60 CellsJournal of Biological Chemistry, 1999