Nature communications, 2020-05, Vol.11 (1), p.2212-2212, Article 2212
2020
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- Autor(en) / Beteiligte
- Titel
- N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis
- Ist Teil von
- Nature communications, 2020-05, Vol.11 (1), p.2212-2212, Article 2212
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Gasdermin-D (GSDMD) in inflammasome-activated macrophages is cleaved by caspase-1 to generate N-GSDMD fragments. N-GSDMD then oligomerizes in the plasma membrane (PM) to form pores that increase membrane permeability, leading to pyroptosis and IL-1β release. In contrast, we report that although N-GSDMD is required for IL-1β secretion in NLRP3-activated human and murine neutrophils, N-GSDMD does not localize to the PM or increase PM permeability or pyroptosis. Instead, biochemical and microscopy studies reveal that N-GSDMD in neutrophils predominantly associates with azurophilic granules and LC3 + autophagosomes. N-GSDMD trafficking to azurophilic granules causes leakage of neutrophil elastase into the cytosol, resulting in secondary cleavage of GSDMD to an alternatively cleaved N-GSDMD product. Genetic analyses using ATG7-deficient cells indicate that neutrophils secrete IL-1β via an autophagy-dependent mechanism. These findings reveal fundamental differences in GSDMD trafficking between neutrophils and macrophages that underlie neutrophil-specific functions during inflammasome activation. In macrophages, IL-1β secretion is mediated by N-GSDMD pores in the plasma membrane (PM). Here the authors show that in neutrophils, IL-1β secretion occurs in the absence of PM pores, via autophagosomes; N-GSDMD does not traffic to PM but to azurophilic granules, thereby releasing neutrophil elastase which cleaves further N-GSDMD into alternative fragments.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-020-16043-9Titel-ID: cdi_doaj_primary_oai_doaj_org_article_e8657a099f0941af8558ca645f8e6b29
- Format
- –
- Schlagworte
- 13/1, 13/106, 13/21, 13/95, 14/19, 14/69, 631/250/127/1213, 631/250/1932, 631/250/2504/223/1699, 631/250/256/2177, 631/80/82/39, Animals, Autophagosomes - metabolism, Autophagy, Autophagy - genetics, Caspase 1 - metabolism, Caspase-1, Cell activation, Cell Membrane - metabolism, Cell Membrane Permeability - genetics, Cytosol, Elastase, Fragments, Genetic analysis, Granular materials, Humanities and Social Sciences, Humans, IL-1β, Inflammasomes, Inflammasomes - metabolism, Interleukin-1beta - metabolism, Intracellular Signaling Peptides and Proteins - genetics, Intracellular Signaling Peptides and Proteins - metabolism, Leukocyte Elastase - genetics, Leukocyte Elastase - metabolism, Leukocytes (neutrophilic), Macrophages, Macrophages - metabolism, Membrane permeability, Membranes, Mice, Inbred C57BL, Mice, Knockout, multidisciplinary, Neutrophils, Neutrophils - metabolism, Oligomerization, Organelles, Organelles - metabolism, Permeability, Phagocytosis, Phagosomes, Phosphate-Binding Proteins - genetics, Phosphate-Binding Proteins - metabolism, Pores, Porosity, Protein Transport, Pyroptosis, Pyroptosis - genetics, Science, Science (multidisciplinary)