The Antimicrobial Peptide CopA3 Inhibits Clostridium difficile Toxin A-Induced Viability Loss and Apoptosis in Neural Cells

Yoon, I Na; Hwang, Jae Sam; Lee, Joon Ha; Kim, Ho

doi:10.4014/jmb.1809.08065

Cited by 5 publications

(2 citation statements)

References 34 publications

(70 reference statements)

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“…Data were analyzed using the SIGMA-STAT professional statistics software program (Jandel Scientific Software, USA). Analyses of variance with protected t test were used for intergroup comparisons [25].…”

Section: Discussionmentioning

confidence: 99%

Clostridium difficile Toxin A Upregulates Bak Expression through PGE2 Pathway in Human Colonocytes

Kim¹,

Kim²

2019

Journal of Microbiology and Biotechnology

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Clostridium difficile toxin A is known to cause colonic epithelial cell apoptosis, which is considered the main causative event that triggers inflammatory responses in the colon, reflecting the concept that the essential role of epithelial cells in the colon is to form a physical barrier in the gut. We previously showed that toxin A-induced colonocyte apoptosis and subsequent inflammation were dependent on prostaglandin E2 (PGE 2) produced in response to toxin A stimulation. However, the molecular mechanism by which PGE 2 mediates cell apoptosis in toxin A-exposed colonocytes has remained unclear. Here, we sought to identify the signaling pathway involved in toxin A-induced, PGE 2-mediated colonocyte apoptosis. In non-transformed NCM460 human colonocytes, toxin A exposure strongly upregulated expression of Bak, which is known to form mitochondrial outer membrane pores, resulting in apoptosis. RT-PCR analyses revealed that this increase in Bak expression was attributable to toxin A-induced transcriptional upregulation. We also found that toxin A upregulation of Bak expression was dependent on PGE 2 production, and further showed that this effect was recapitulated by an Prostaglandin E2(PGE2) receptor-1 receptor agonist, but not by agonists of other EP receptors. Collectively, these results suggest that toxin A-induced cell apoptosis involves PGE 2-upregulation of Bak through the EP1 receptor.

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Section: Discussionmentioning

confidence: 99%

Clostridium difficile Toxin A Upregulates Bak Expression through PGE2 Pathway in Human Colonocytes

Kim¹,

Kim²

2019

Journal of Microbiology and Biotechnology

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“…The CopA3 peptide (LLCIAALRKK, homodimer), isolated from the Dung beetle, Copris tripartitus), and a CopA3-CA mutant, in which a cysteine in CopA3 was replaced with alanine, were synthesized by AnyGen (Korea) [15]. CopA3-deletion mutants (a leucine-deleted mutant: LLCIALRKK, a lysine-deleted mutant: LLCIALRKK, a two lysine deleted-mutant: LLCIALRKK, an arginine and two lysines-deleted mutant: LLCIALRKK, an C-terminal four amino acids-deleted CopA3 mutant: LLCIALRKK, an C-terminal five amino acids-deleted CopA3 mutant: LLCIALRKK, an C-terminal six amino acids-deleted CopA3 mutant: LLCIALRKK).…”

Section: Synthesis Of Copa3 Copa3-cysteine Mutant and Other Antimicro...mentioning

confidence: 99%

The Specific Binding Mechanism of the Antimicrobial Peptide CopA3 to Caspases

Kim

2023

Microbiol. Biotechnol. Lett.

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We recently found that the insect-derived antimicrobial peptide CopA3 (LLCIALRKK) directly binds to and inhibits the proteolytic activation of caspases, which play essential roles in apoptotic processes. However, the mechanism of CopA3 binding to caspases remained unknown. Here, using recombinant GST-caspase-3 and -6 proteins, we investigated the mechanism by which CopA3 binds to caspases. We showed that replacement of cysteine in CopA3 with alanine caused a marked loss in its binding activity towards caspase-3 and -6. Exposure to DTT, a reducing agent, also diminished their interaction, suggesting that this cysteine plays an essential role in caspase binding. Experiments using deletion mutants of CopA3 showed that the last N-terminal leucine residue of CopA3 peptide is required for binding of CopA3 to caspases, and that C-terminal lysine and arginine residues also contribute to their interaction. These conclusions are supported by binding experiments employing direct addition of CopA3 deletion mutants to human colonocyte (HT29) extracts containing endogenous caspase-3 and -6 proteins. In summary, binding of CopA3 to caspases is dependent on a cysteine in the intermediate region of the CopA3 peptide and a leucine in the Nterminal region, but that both an arginine and two adjacent lysines in the C-terminal region of CopA3 also contribute. Collectively, these results provide insight into the interaction mechanism and the high selectivity of CopA3 for caspases.

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Whether short peptides are good candidates for future neuroprotective therapeutics?

Perlikowska

2021

Peptides

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The Antimicrobial Peptide CopA3 Inhibits Clostridium difficile Toxin A-Induced Viability Loss and Apoptosis in Neural Cells

Cited by 5 publications

References 34 publications

Clostridium difficile Toxin A Upregulates Bak Expression through PGE2 Pathway in Human Colonocytes

Clostridium difficile Toxin A Upregulates Bak Expression through PGE2 Pathway in Human Colonocytes

The Specific Binding Mechanism of the Antimicrobial Peptide CopA3 to Caspases

Whether short peptides are good candidates for future neuroprotective therapeutics?

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