Molecular Characteristics of Clostridium perfringens TpeL Toxin and Consequences of Mono-O-GlcNAcylation of Ras in Living Cells

Abstract

Background: TpeL is a member of the family of clostridial glucosylating toxins, produced by Clostridium perfringens. Results: TpeL enters target cells by self-mediated entry and mono-glycosylates Ras proteins at Thr-35. Conclusion: TpeL inhibits Ras signaling and induces apoptosis in target cells. Significance: TpeL is a new glucosylating toxin produced by C. perfringens.

<i>Clostridium perfringens</i> TpeL Induces Formation of Stress Fibers <i>via</i> Activation of RhoA-ROCK Signaling Pathway

“…TpeL was previously shown to be the cytotoxic to Vero cells and induced apoptosis in HeLa cells. 8,11) It has not been reported whether other LCTs can induce formation of stress fiber. The results of the present study indicated that the low-dose TpeL induced the formation of stress fibers in host cells.…”

“…11,12,15) Guttenberg et al 11) reported that inhibiting the Ras signaling pathway by TpeL was essential for the induction of apoptosis. However, in the present study, we showed that the treatment of cells with low concentrations of TpeL that were insufficient to evoke cytopathic effects resulted in an increase in the formation of stress fibers in a dose-dependent manner.…”

“…e-mail: nagahama@ph.bunri-u.ac.jp and HeLa cells. 8,11) This toxin also blocked Ras signaling pathways in rat phenochromocytoma PC12 cells.…”

“…8,11,12) LCTs are thought to bind to the membrane receptor of sensitive cells. 13,14) After endocytosis, cellular inositolhexaphosphate (InsP 6 )-dependent cysteine protease cleavage, and transport across the endosomal membrane, the catalytic domain internalizes the cytolasm from early endosomes.…”

“…TpeL is the sole LCT that can use both uridine 5′-diphosphate (UDP)-glucose and UDP-N-acetylglucosamine as donor substrates. 11,12,15) TpeL modifies the Rac1 and Ras subfamily by glucosylation in order to concern its cytotoxic activities. Blokade of the Ras signaling pathway was previously shown to be essential for TpeL-caused apoptosis.…”