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Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD
Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, c...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Life Science Alliance LLC
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190276/ https://www.ncbi.nlm.nih.gov/pubmed/32345661 http://dx.doi.org/10.26508/lsa.202000735 |
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author | Heilig, Rosalie Dilucca, Marisa Boucher, Dave Chen, Kaiwen W Hancz, Dora Demarco, Benjamin Shkarina, Kateryna Broz, Petr |
author_facet | Heilig, Rosalie Dilucca, Marisa Boucher, Dave Chen, Kaiwen W Hancz, Dora Demarco, Benjamin Shkarina, Kateryna Broz, Petr |
author_sort | Heilig, Rosalie |
collection | PubMed |
description | Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, caspase-1 activates apoptotic initiator and executioner caspases and triggers a rapid progression into secondary necrosis. GSDMD-independent cell death required direct caspase-1–driven truncation of Bid and generation of caspase-3 p19/p12 by either caspase-8 or caspase-9. tBid-induced mitochondrial outer membrane permeabilization was also required to drive SMAC release and relieve inhibitor of apoptosis protein inhibition of caspase-3, thereby allowing caspase-3 auto-processing to the fully active p17/p12 form. Our data reveal that cell lysis in inflammasome-activated Gsdmd-deficient cells is caused by a synergistic effect of rapid caspase-1–driven activation of initiator caspases-8/-9 and Bid cleavage, resulting in an unusually fast activation of caspase-3 and immediate transition into secondary necrosis. This pathway might be advantageous for the host in counteracting pathogen-induced inhibition of GSDMD but also has implications for the use of GSDMD inhibitors in immune therapies for caspase-1–dependent inflammatory disease. |
format | Online Article Text |
id | pubmed-7190276 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Life Science Alliance LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-71902762020-05-06 Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD Heilig, Rosalie Dilucca, Marisa Boucher, Dave Chen, Kaiwen W Hancz, Dora Demarco, Benjamin Shkarina, Kateryna Broz, Petr Life Sci Alliance Research Articles Caspase-1 drives a lytic inflammatory cell death named pyroptosis by cleaving the pore-forming cell death executor gasdermin-D (GSDMD). Gsdmd deficiency, however, only delays cell lysis, indicating that caspase-1 controls alternative cell death pathways. Here, we show that in the absence of GSDMD, caspase-1 activates apoptotic initiator and executioner caspases and triggers a rapid progression into secondary necrosis. GSDMD-independent cell death required direct caspase-1–driven truncation of Bid and generation of caspase-3 p19/p12 by either caspase-8 or caspase-9. tBid-induced mitochondrial outer membrane permeabilization was also required to drive SMAC release and relieve inhibitor of apoptosis protein inhibition of caspase-3, thereby allowing caspase-3 auto-processing to the fully active p17/p12 form. Our data reveal that cell lysis in inflammasome-activated Gsdmd-deficient cells is caused by a synergistic effect of rapid caspase-1–driven activation of initiator caspases-8/-9 and Bid cleavage, resulting in an unusually fast activation of caspase-3 and immediate transition into secondary necrosis. This pathway might be advantageous for the host in counteracting pathogen-induced inhibition of GSDMD but also has implications for the use of GSDMD inhibitors in immune therapies for caspase-1–dependent inflammatory disease. Life Science Alliance LLC 2020-04-28 /pmc/articles/PMC7190276/ /pubmed/32345661 http://dx.doi.org/10.26508/lsa.202000735 Text en © 2020 Heilig et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Heilig, Rosalie Dilucca, Marisa Boucher, Dave Chen, Kaiwen W Hancz, Dora Demarco, Benjamin Shkarina, Kateryna Broz, Petr Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD |
title | Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD |
title_full | Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD |
title_fullStr | Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD |
title_full_unstemmed | Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD |
title_short | Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD |
title_sort | caspase-1 cleaves bid to release mitochondrial smac and drive secondary necrosis in the absence of gsdmd |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190276/ https://www.ncbi.nlm.nih.gov/pubmed/32345661 http://dx.doi.org/10.26508/lsa.202000735 |
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