Anthrax lethal toxin paralyzes actin-based motility by blocking Hsp27 phosphorylation.

Area of Science:

• Microbiology
• Immunology
• Cell Biology

Background:

• Inhalation anthrax leads to fatal bacteremia due to a weak host immune response.
• Anthrax lethal toxin (LT) is known to paralyze neutrophils, crucial cells in innate immunity.

Purpose of the Study:

• To investigate the effect of anthrax lethal toxin (LT) on the actin-based motility of intracellular Listeria monocytogenes.
• To elucidate the role of Hsp27 phosphorylation in LT-mediated inhibition of bacterial motility and its implications for innate immunity.

Main Methods:

• Utilized cell extracts and purified actin monomers to study the interaction between Hsp27 and actin.
• Employed RNA interference (RNAi) to knock down Hsp27 expression and rescue experiments with wild-type and mutant Hsp27.
• Investigated the role of p38 mitogen-activated protein (MAP) kinase pathway by using the inhibitor SB203580.

Main Results:

• LT inhibits Listeria actin-based motility by blocking Hsp27 phosphorylation, a process mimicked by p38 MAP kinase inhibition.
• Nonphosphorylated Hsp27 sequesters actin monomers, hindering motility, while phosphorylation reverses this effect.
• Hsp27 knockdown prevents LT-induced inhibition of Listeria motility, and Hsp27 phosphorylation is essential for facilitating motility.

Conclusions:

• Hsp27 phosphorylation is critical for actin-based motility, potentially by facilitating actin monomer transport.
• LT employs a novel virulence mechanism by disrupting the Hsp27 phosphorylation cycle, impairing neutrophil function.
• p38 MAP kinase-mediated Hsp27 phosphorylation plays a central role in actin-based motility and innate immune responses.