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N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis
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-GS...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200749/ https://www.ncbi.nlm.nih.gov/pubmed/32371889 http://dx.doi.org/10.1038/s41467-020-16043-9 |
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author | Karmakar, Mausita Minns, Martin Greenberg, Elyse N. Diaz-Aponte, Jose Pestonjamasp, Kersi Johnson, Jennifer L. Rathkey, Joseph K. Abbott, Derek W. Wang, Kun Shao, Feng Catz, Sergio D. Dubyak, George R. Pearlman, Eric |
author_facet | Karmakar, Mausita Minns, Martin Greenberg, Elyse N. Diaz-Aponte, Jose Pestonjamasp, Kersi Johnson, Jennifer L. Rathkey, Joseph K. Abbott, Derek W. Wang, Kun Shao, Feng Catz, Sergio D. Dubyak, George R. Pearlman, Eric |
author_sort | Karmakar, Mausita |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7200749 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-72007492020-05-07 N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis Karmakar, Mausita Minns, Martin Greenberg, Elyse N. Diaz-Aponte, Jose Pestonjamasp, Kersi Johnson, Jennifer L. Rathkey, Joseph K. Abbott, Derek W. Wang, Kun Shao, Feng Catz, Sergio D. Dubyak, George R. Pearlman, Eric Nat Commun Article 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. Nature Publishing Group UK 2020-05-05 /pmc/articles/PMC7200749/ /pubmed/32371889 http://dx.doi.org/10.1038/s41467-020-16043-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Karmakar, Mausita Minns, Martin Greenberg, Elyse N. Diaz-Aponte, Jose Pestonjamasp, Kersi Johnson, Jennifer L. Rathkey, Joseph K. Abbott, Derek W. Wang, Kun Shao, Feng Catz, Sergio D. Dubyak, George R. Pearlman, Eric N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis |
title | N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis |
title_full | N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis |
title_fullStr | N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis |
title_full_unstemmed | N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis |
title_short | N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis |
title_sort | n-gsdmd trafficking to neutrophil organelles facilitates il-1β release independently of plasma membrane pores and pyroptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200749/ https://www.ncbi.nlm.nih.gov/pubmed/32371889 http://dx.doi.org/10.1038/s41467-020-16043-9 |
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