Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-04, Vol.106 (17), p.7179-7184
• Main Authors: Orth, Joachim H.C, Preuss, Inga, Fester, Ines, Schlosser, Andreas, Wilson, Brenda A, Aktories, Klaus
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - metabolism; amide hydrolases; Amino Acid Sequence; animal pathogenic bacteria; Animals; Bacteria; Bacterial proteins; Bacterial Proteins - metabolism; bacterial toxins; Bacterial Toxins - metabolism; Biological Sciences; Cell membranes; Cells, Cultured; chemical reactions; deamidation; Deamination; Electrophoresis; enzyme activity; Escherichia coli - genetics; Escherichia coli - metabolism; G-proteins; Gels; Gene Expression Regulation; glutamic acid; glutamine; Heterotrimeric GTP-Binding Proteins - metabolism; Hydrolysis; Inositol phosphates; Mice; Pasteurella multocida; Predetermined motion time systems; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Signal transduction; Tandem Mass Spectrometry; toxicity; Toxins; Whooping cough
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0900160106

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 [almost equal to]145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the Gαq, Gαi, and Gα₁₂/₁₃ families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of Gαi₂ to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of Gαi and causes persistent activation of the G protein. A similar modification is also evident for Gαq, but not for the closely related Gα₁₁, which is not a substrate of Pasteurella multocida toxin. Our data identify the α-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.