Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.

Programmed necrosis is a mechanism of cell death that has been described for neuronal excitotoxicity and ischemia/reperfusion injury, but has not been extensively studied in the context of exposure to bacterial exotoxins. The alpha-toxin of Clostridium septicum is a beta-barrel pore-forming toxin an...

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Autores principales:	Catherine L Kennedy, Danielle J Smith, Dena Lyras, Anjana Chakravorty, Julian I Rood
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/fabebe6493934b419f2b90473bf4f3ab
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spelling	oai:doaj.org-article:fabebe6493934b419f2b90473bf4f3ab2021-11-25T05:47:46ZProgrammed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.1553-73661553-737410.1371/journal.ppat.1000516https://doaj.org/article/fabebe6493934b419f2b90473bf4f3ab2009-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19609357/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Programmed necrosis is a mechanism of cell death that has been described for neuronal excitotoxicity and ischemia/reperfusion injury, but has not been extensively studied in the context of exposure to bacterial exotoxins. The alpha-toxin of Clostridium septicum is a beta-barrel pore-forming toxin and a potent cytotoxin; however, the mechanism by which it induces cell death has not been elucidated in detail. We report that alpha-toxin formed Ca(2+)-permeable pores in murine myoblast cells, leading to an increase in intracellular Ca(2+) levels. This Ca(2+) influx did not induce apoptosis, as has been described for other small pore-forming toxins, but a cascade of events consistent with programmed necrosis. Ca(2+) influx was associated with calpain activation and release of cathepsins from lysosomes. We also observed deregulation of mitochondrial activity, leading to increased ROS levels, and dramatically reduced levels of ATP. Finally, the immunostimulatory histone binding protein HMGB1 was found to be released from the nuclei of alpha-toxin-treated cells. Collectively, these data show that alpha-toxin initiates a multifaceted necrotic cell death response that is consistent with its essential role in C. septicum-mediated myonecrosis and sepsis. We postulate that cellular intoxication with pore-forming toxins may be a major mechanism by which programmed necrosis is induced.Catherine L KennedyDanielle J SmithDena LyrasAnjana ChakravortyJulian I RoodPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 7, p e1000516 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Catherine L Kennedy Danielle J Smith Dena Lyras Anjana Chakravorty Julian I Rood Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.
description	Programmed necrosis is a mechanism of cell death that has been described for neuronal excitotoxicity and ischemia/reperfusion injury, but has not been extensively studied in the context of exposure to bacterial exotoxins. The alpha-toxin of Clostridium septicum is a beta-barrel pore-forming toxin and a potent cytotoxin; however, the mechanism by which it induces cell death has not been elucidated in detail. We report that alpha-toxin formed Ca(2+)-permeable pores in murine myoblast cells, leading to an increase in intracellular Ca(2+) levels. This Ca(2+) influx did not induce apoptosis, as has been described for other small pore-forming toxins, but a cascade of events consistent with programmed necrosis. Ca(2+) influx was associated with calpain activation and release of cathepsins from lysosomes. We also observed deregulation of mitochondrial activity, leading to increased ROS levels, and dramatically reduced levels of ATP. Finally, the immunostimulatory histone binding protein HMGB1 was found to be released from the nuclei of alpha-toxin-treated cells. Collectively, these data show that alpha-toxin initiates a multifaceted necrotic cell death response that is consistent with its essential role in C. septicum-mediated myonecrosis and sepsis. We postulate that cellular intoxication with pore-forming toxins may be a major mechanism by which programmed necrosis is induced.
format	article
author	Catherine L Kennedy Danielle J Smith Dena Lyras Anjana Chakravorty Julian I Rood
author_facet	Catherine L Kennedy Danielle J Smith Dena Lyras Anjana Chakravorty Julian I Rood
author_sort	Catherine L Kennedy
title	Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.
title_short	Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.
title_full	Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.
title_fullStr	Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.
title_full_unstemmed	Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.
title_sort	programmed cellular necrosis mediated by the pore-forming alpha-toxin from clostridium septicum.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/fabebe6493934b419f2b90473bf4f3ab
work_keys_str_mv	AT catherinelkennedy programmedcellularnecrosismediatedbytheporeformingalphatoxinfromclostridiumsepticum AT daniellejsmith programmedcellularnecrosismediatedbytheporeformingalphatoxinfromclostridiumsepticum AT denalyras programmedcellularnecrosismediatedbytheporeformingalphatoxinfromclostridiumsepticum AT anjanachakravorty programmedcellularnecrosismediatedbytheporeformingalphatoxinfromclostridiumsepticum AT julianirood programmedcellularnecrosismediatedbytheporeformingalphatoxinfromclostridiumsepticum
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Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.

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