Cytolethal Distending Toxin-Increased DNA Damage and Ploidy Involve the YAP/TAZ-TEAD Signaling Pathway

Area of Science:

• Microbiology
• Molecular Biology
• Cell Biology

Background:

• Bacterial genotoxins, including CDT and colibactin, induce significant DNA damage and genomic instability in host cells.
• These genotoxins disrupt DNA damage response pathways.
• Observed cellular phenotypes suggest a potential link between genotoxin effects and the Hippo signaling pathway.

Purpose of the Study:

• To investigate the role of the Hippo signaling pathway in epithelial cells following intoxication with CDT/CdtB and colibactin.
• To elucidate the molecular mechanisms by which bacterial genotoxins impact host cell signaling and genomic integrity.

Main Methods:

• Utilized normal and cancer-derived epithelial intestinal and hepatic cell lines.
• Exposed cells to CDT/CdtB and colibactin.
• Analyzed Hippo pathway components, including YAP/TAZ and TEAD-mediated transcription.
• Assessed effects of inhibiting YAP/TAZ-TEAD binding on DNA damage, repair, and ploidy.

Main Results:

• The active CdtB subunit of CDT modulates YAP/TAZ expression and increases TEAD-mediated transcription.
• Inhibiting YAP/TAZ-TEAD binding with verteporfin and K-975 reduced DNA damage, impaired repair, and decreased ploidy.
• Colibactin exposure induced similar effects on the YAP/TAZ-TEAD pathway and cellular phenotypes.
• YAP/TAZ-TEAD signaling is implicated in increased ploidy in cells surviving CDT/CdtB-induced DNA damage.

Conclusions:

• Genotoxin-producing bacterial infections engage the YAP/TAZ-TEAD signaling pathway.
• This pathway plays a critical role in regulating ploidy following DNA damage in epithelial cells.
• The findings highlight a novel mechanism by which bacteria manipulate host cell processes to promote genomic instability.