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  • Title: Oligomer formation of Clostridium perfringens epsilon-toxin is induced by activation of neutral sphingomyelinase.
    Author: Takagishi T, Oda M, Takehara M, Kobayashi K, Nagahama M.
    Journal: Biochim Biophys Acta; 2016 Nov; 1858(11):2681-2688. PubMed ID: 27453200.
    Abstract:
    BACKGROUND: Clostridium perfringens epsilon-toxin is responsible for fatal enterotoxemia in ungulates. The toxin forms a heptamer in the lipid rafts of Madin-Darby Canine Kidney (MDCK) cells, leading to cell death. Here, we showed that epsilon-toxin requires neutral sphingomyelinase (nSMase) activity during oligomerization. METHODS: We tested the role of nSMase in the oligomerization of epsilon-toxin using specific inhibitors, knockdown of nSMase, formation of ceramide, and localization of epsilon-toxin and ceramide by immunofluorescence staining. RESULTS: Epsilon-toxin induced the production of ceramide is a dose- and time-dependent manner in ACHN cells. GW4869, an inhibitor of nSMase, inhibited ceramide production induced by the toxin. GW4869 and knockdown of nSMase blocked toxin-induced cell death and oligomer formation of epsilon-toxin. Confocal microscopy images showed that the toxin induced ceramide clustering and colocalized with ceramide. CONCLUSIONS: These results demonstrated that oligomer formation of epsilon-toxin is facilitated by the production of ceramide through activation of nSMase caused by the toxin. GENERAL SIGNIFICANCE: Inhibitors of nSMase may confer protection against infection.
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