Pore-forming toxins activate MAPK p38 by causing loss of cellular potassium

Area of Science:

• Cellular biology
• Molecular signaling
• Microbiology

Background:

• Mitogen-activated protein kinase (MAPK) p38 acts as a survival protein in cells targeted by bacterial pore-forming toxins (PFTs).
• Previous hypotheses suggested osmotic stress as the primary activator of p38 MAPK by PFTs.

Purpose of the Study:

• To investigate the precise mechanism by which PFTs activate the p38 MAPK pathway.
• To determine whether potassium (K+) loss or osmotic stress is the critical factor in p38 MAPK activation by PFTs.

Main Methods:

• Cells were exposed to alpha-toxin with and without osmoprotection.
• Cells were treated with a K+ ionophore or incubated in K+-free medium.
• Cells were treated with various PFTs (alpha-toxin, VCC, SLO, HlyA) in media with varying K+ concentrations.
• Cells were treated with hydrogen peroxide (H2O2) as a control.

Main Results:

• Osmoprotection did not prevent p38 MAPK phosphorylation in toxin-exposed cells.
• K+ ionophore treatment and K+-free medium induced robust p38 MAPK phosphorylation.
• High extracellular K+ prevented p38 MAPK activation by multiple PFTs but not by H2O2.
• Roles of LPS, TLR4, and calcium influx were excluded.

Conclusions:

• Cellular K+ loss, rather than osmotic stress, is the critical parameter triggering p38 MAPK activation by PFTs.
• PFTs likely activate the p38 MAPK pathway through the induction of cellular K+ efflux.