Contractile actin cables induced by Bacillus anthracis lethal toxin depend on the histone acetylation machinery

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Actin cytoskeleton rearrangements are crucial for cell structure and function.
• Gene expression reprogramming influences long-term cellular changes.
• Bacillus anthracis lethal toxin (LT) disrupts endothelial barrier function by inhibiting MAPK signaling.

Purpose of the Study:

• To investigate the molecular mechanisms underlying LT-induced actin cytoskeleton alterations.
• To characterize the mechanical properties of LT-induced stress fibers.
• To explore the role of protein acetylation in regulating endothelial barrier integrity.

Main Methods:

• Laser ablation to assess mechanical properties of stress fibers.
• Treatment with histone deacetylase (HDAC) inhibitors (TSA, MS-275) and histone acetyl-transferase (HAT) inhibitor (garcinol).
• Analysis of gene expression (Rnd3) and protein acetylation levels.

Main Results:

• LT intoxication leads to stress fiber formation and reduced HDAC activity.
• HDAC inhibition (TSA, MS-275) induces stress fibers, while HAT inhibition (garcinol) disrupts them.
• Rnd3 expression is induced by both LT and TSA, and is required for LT-mediated stress fiber formation.
• Modulating protein acetylation impacts endothelial barrier function.

Conclusions:

• Protein acetylation flux is critical for controlling actin cytoskeleton organization.
• Targeting protein acetylation pathways offers a strategy to restore endothelial monolayer barrier function.
• HDACs and HATs play key roles in regulating LT-induced cellular responses.