Reference - Detail
RRC ID | 51882 |
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Author | Seike S, Takehara M, Kobayashi K, Nagahama M. |
Title | Role of pannexin 1 in Clostridium perfringens beta-toxin-caused cell death. |
Journal | Biochim Biophys Acta |
Abstract |
BACKGROUND:Beta-toxin produced by Clostridium perfringens is a key virulence factor of fatal hemorrhagic enterocolitis and enterotoxemia. This toxin belongs to a family of β-pore-forming toxins (PFTs). We reported recently that the ATP-gated P2X7 receptor interacts with beta-toxin. The ATP-release channel pannexin 1 (Panx1) is an important contributor to P2X7 receptor signaling. Hence, we investigated the involvement of Panx1 in beta-toxin-caused cell death. METHODS:We examined the effect of Panx1 in beta-toxin-induced cell death utilizing selective antagonists, knockdown of Panx1, and binding using dot-blot analysis. Localization of Panx1 and the P2X7 receptor after toxin treatment was determined by immunofluorescence staining. RESULTS:Selective Panx1 antagonists (carbenoxolone [CBX], probenecid, and Panx1 inhibitory peptide) prevented beta-toxin-caused cell death in THP-1 cells. CBX did not block the binding of the toxin to cells. Small interfering knockdown of Panx1 blocked beta-toxin-mediated cell death through inhibiting the oligomer formation of the toxin. Beta-toxin triggered a transient ATP release from THP-1 cells, but this early ATP release was blocked by CBX. ATP scavengers (apyrase and hexokinase) inhibited beta-toxin-induced cytotoxicity. Furthermore, co-administration of ATP with beta-toxin enhanced the binding and cytotoxicity of the toxin. CONCLUSIONS:Based on our results, Panx1 activation is achieved through the interaction of beta-toxin with the P2X7 receptor. Then, ATP released by the Panx1 channel opening promotes oligomer formation of the toxin, leading to cell death. GENERAL SIGNIFICANCE:Pannexin 1 is a novel candidate therapeutic target for beta-toxin-mediated disease. |
Volume | 1858(12) |
Pages | 3150-3156 |
Published | 2016-12-1 |
DOI | 10.1016/j.bbamem.2016.10.003 |
PII | S0005-2736(16)30330-3 |
PMID | 27720686 |
MeSH | Adenosine Triphosphate / metabolism Apyrase / pharmacology Bacterial Toxins / toxicity* Carbenoxolone / pharmacology Cell Death / drug effects Cells, Cultured Connexins / physiology* Hexokinase / pharmacology Humans Nerve Tissue Proteins / physiology* Receptors, Purinergic P2X7 / physiology |
IF | 3.411 |
Times Cited | 7 |
Resource | |
Human and Animal Cells | THP-1(RCB1189) |