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Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation.

ABSTRACT: Pasteurella multocida toxin is a major virulence factor of Pasteurella multocida, which causes pasteurellosis in men and animals and atrophic rhinitis in rabbits and pigs. The approximately 145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the Galpha(q), Galpha(i), and Galpha(12/13) families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of Galpha(i2) to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of Galpha(i) and causes persistent activation of the G protein. A similar modification is also evident for Galpha(q), but not for the closely related Galpha(11), which is not a substrate of Pasteurella multocida toxin. Our data identify the alpha-subunits of heterotrimeric G proteins as the direct molecular target of Pasteurella multocida toxin and indicate that the toxin does not act like a protease, which was suggested from its thiol protease-like catalytic triad, but instead causes constitutive activation of G proteins by deamidase activity.

SUBMITTER: Orth JH

PROVIDER: S-EPMC2678484 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation.

Orth Joachim H C JH Preuss Inga I Fester Ines I Schlosser Andreas A Wilson Brenda A BA Aktories Klaus K

Proceedings of the National Academy of Sciences of the United States of America 20090415 17

Pasteurella multocida toxin is a major virulence factor of Pasteurella multocida, which causes pasteurellosis in men and animals and atrophic rhinitis in rabbits and pigs. The approximately 145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the Galpha(q), Galpha(i), and Galpha(12/13) families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of Galpha(i2) to glutamic acid. Th ...[more]

PMID: 19369209

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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

Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation.

Publications

Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation.

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