Programmed Cellular Necrosis Mediated by the Pore-Forming α-Toxin from Clostridium septicum

PLoS Pathogens

Anjana Chakravorty¹  Catherine L. Kennedy¹  Julian I. Rood¹  Danielle J. Smith²  Dena Lyras³ 

[1] Australian Bacterial Pathogenesis Research Program, Department of Microbiology, Monash University, Clayton, Victoria, Australia;Australian Research Council Centre for Excellence in Structural and Functional Microbial Genomics, Department of Microbiology, Monash University, Clayton, Victoria, Australia;Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

关键词: Apoptosis;    Necrosis;    Toxins;    Lysosomes;    Necrotic cell death;    Cell staining;    Mitochondria;    Myoblasts;   

DOI  :  10.1371/journal.ppat.1000516

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 α-toxin of Clostridium septicum is a β-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 α-toxin formed Ca2+-permeable pores in murine myoblast cells, leading to an increase in intracellular Ca2+ levels. This Ca2+ influx did not induce apoptosis, as has been described for other small pore-forming toxins, but a cascade of events consistent with programmed necrosis. Ca2+ 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 α-toxin-treated cells. Collectively, these data show that α-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.

【 授权许可】

CC BY