Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation

Pasteurella multocida toxin is a major virulence factor of Pasteu-rella multocida, which causes pasteurellosis in men and animals and atrophic rhinitis in rabbits and pigs. The ≈145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the Gα _q, Gα _q and Gα _12/13 families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of Gα _i2 to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of Gα _i; and causes persistent activation of the G protein. A similar modification is also evident for Gα _q, but not for the closely related Gα ₁₁, 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.