Cellular and molecular action of the mitogenic protein-deamidating toxin from Pasteurella multocida

The mitogenic toxin from Pasteurella multocida (PMT) is a member of the dermonecrotic toxin family, which includes toxins from Bordetella, Escherichia coli and Yersinia. Members of the dermonecrotic toxin family modulate G-protein targets in host cells through selective deamidation and/or transglutamination of a critical active site Gln residue in the G-protein target, which results in the activation of intrinsic GTPase activity. Structural and biochemical data point to the uniqueness of PMT among these toxins in its structure and action. Whereas the other dermonecrotic toxins act on small Rho GTPases, PMT acts on the a subunits of heterotrimeric Gq-, Gi- and G12/13-protein families. To date, experimental evidence supports a model in which PMT potently stimulates various mitogenic and survival pathways through the activation of Gq and G12/13 signaling, ultimately leading to cellular proliferation, whilst strongly inhibiting pathways involved in cellular differentiation through the activation of Gi signaling. The resulting cellular outcomes account for the global physiological effects observed during infection with toxinogenic P. multocida, and hint at potential long-term sequelae that may result from PMT exposure.