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machinery responsible for orchestrating the transfer of phagosomes into phagolysosomes, where bacteria can be eliminated.
Nevertheless, intracellular pathogens are rather successful in preventing intracellular elimination. The activation of Irgm1 critically depends on the activation of PI(3)K to generate phosphatidylinositol-3,4,5-trisphosphate, which in turn activates the kinase Akt1. Akt1 is involved in many cellular responses, including cell survival and cell growth. Notably, Akt1 is directly activated by various pathogens such as Salmonella typhimurium6 and Mycobacterium tuberculosis7,8. Akt1 is important for the intracellular survival of these bacteria, as activated Akt1 phosphorylates AS160, which is the activating protein for the GTPase Rab14. Phosphorylation renders AS160 unable to interact with phagosomal membranes and therefore unable to inactivate Rab14. As a consequence, Rab14 remains active on phagosomal membranes and prevents the transfer of bacteria from phagosomes to lysosomes by an asyet-unknown mechanism8 (Fig. 1).
This all seems counterintuitive, as activation of PI(3)K both supports (through activation of Igrm1) and inhibits (through activation of Rab14) the elimination of intracellular patho-
gens (Fig. 1). However, bacteria might have identified the Akt system early in evolution as an Achilles heel of host cell biology. If so, the pathway of Akt1, AS160 and Rab14 should be older, in evolutionary terms, than the IRG GTPases. Indeed Akt1, AS160 and Rab14 are present in invertebrates such as insects. The IRG GTPases, however, may be a more recent evolutionary development, as they are present only in vertebrates9. It is possible that IRG GTPases arose in response to the bacterial strategy of promoting intracellular survival by competing with the Akt1 system. By using the same phosphoinositides, the IRG GTPases generated a defense system that overrides the system used by many pathogens for intracellular survival. Pathogens probably cannot easily exchange the Akt1 system for an alternative system, as they depend on it for their survival (Fig. 1).
According to the Red Queen hypothesis10,
it can be predicted that pathogens under evolutionary pressure will develop systems to manipulate the IRG GTPases. However, it is possible that the different IRG GTPases can compensate for each other. If these GTPases have different activating proteins, guanine nucleotideexchange factors and effector proteins, definitive inactivation of this sys-
tem will be complicated. Any new...