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

ABSTRACT: 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 ? subunits of heterotrimeric G(q) -, G(i) - and G(12/13) -protein families. To date, experimental evidence supports a model in which PMT potently stimulates various mitogenic and survival pathways through the activation of G(q) and G(12/13) signaling, ultimately leading to cellular proliferation, whilst strongly inhibiting pathways involved in cellular differentiation through the activation of G(i) 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.

SUBMITTER: Wilson BA

PROVIDER: S-EPMC3166354 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

Wilson Brenda A BA Ho Mengfei M

The FEBS journal 20110531 23

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 amo ...[more]

PMID: 21569202

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Project description:Bone remodeling is a continuous process to retain the structural integrity and function of the skeleton. A tight coupling is maintained between osteoclast-mediated resorption of old or damaged bones and osteoblast-mediated formation of new bones for bone homeostasis. While osteoblasts differentiate from mesenchymal stem cells, osteoclasts are hematopoietic in origin and derived from myeloid precursor cells. Osteoclast differentiation is driven by two cytokines, cytokine receptor activator of NF-κB ligand (RANKL), and macrophage colony-stimulating factor. Imbalances in the activity of osteoblasts and osteoclasts result in the development of bone disorders. Bacterially caused porcine atrophic rhinitis is characterized by a loss of nasal ventral conche bones and a distortion of the snout. While Bordetella bronchiseptica strains cause mild and reversible symptoms, infection of pigs with toxigenic Pasteurella multocida strains causes a severe and irreversible decay. The responsible virulence factor Pasteurella multocida toxin (PMT) contains a deamidase activity in its catalytical domain that constitutively activates specific heterotrimeric G proteins to induce downstream signaling cascades. While osteoblasts are inhibited by the toxin, osteoclasts are activated, thus skewing bone remodeling toward excessive bone degradation. Still, the mechanism by which PMT interferes with bone homeostasis, and the reason for this unusual target tissue is not yet well understood. Here, we show that PMT has the potential to differentiate bone marrow-derived macrophages into functional osteoclasts. This toxin-mediated differentiation process is independent of RANKL, a cytokine believed to be indispensable for triggering osteoclastogenesis, as addition of osteoprotegerin to PMT-treated macrophages does not show any effect on PMT-induced osteoclast formation. Although RANKL is not a prerequisite, toxin-primed macrophages show enhanced responsiveness to low concentrations of RANKL, suggesting that the PMT-generated microenvironment offers conditions where low concentrations of RANKL lead to an increase in the number of osteoclasts resulting in increased resorption. PMT-mediated release of the osteoclastogenic cytokines such as IL-6 and TNF-α, but not IL-1, supports the differentiation process. Although the production of cytokines and the subsequent activation of signaling cascades are necessary for PMT-mediated differentiation into osteoclasts, they are not sufficient and PMT-induced activation of G protein signaling is essential for efficient osteoclastogenesis.

Dataset Information

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

Publications

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

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