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http://purl.uniprot.org/citations/27720686http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27720686http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/27720686http://purl.org/dc/terms/identifier"doi:10.1016/j.bbamem.2016.10.003"xsd:string
http://purl.uniprot.org/citations/27720686http://purl.uniprot.org/core/author"Kobayashi K."xsd:string
http://purl.uniprot.org/citations/27720686http://purl.uniprot.org/core/author"Takehara M."xsd:string
http://purl.uniprot.org/citations/27720686http://purl.uniprot.org/core/author"Nagahama M."xsd:string
http://purl.uniprot.org/citations/27720686http://purl.uniprot.org/core/author"Seike S."xsd:string
http://purl.uniprot.org/citations/27720686http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/27720686http://purl.uniprot.org/core/name"Biochim Biophys Acta"xsd:string
http://purl.uniprot.org/citations/27720686http://purl.uniprot.org/core/pages"3150-3156"xsd:string
http://purl.uniprot.org/citations/27720686http://purl.uniprot.org/core/title"Role of pannexin 1 in Clostridium perfringens beta-toxin-caused cell death."xsd:string
http://purl.uniprot.org/citations/27720686http://purl.uniprot.org/core/volume"1858"xsd:string
http://purl.uniprot.org/citations/27720686http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/27720686
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