Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation

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 approximate to 145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the G alpha(q), G alpha(i), and G alpha(12/13) families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of G alpha(i2) to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of G alpha(i) and causes persistent activation of the G protein. A similar modification is also evident for G alpha(q), but not for the closely related G alpha(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.