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Several bacterial pathogens secrete proteins into the host cells that act as GTPase‐activating proteins (GAPs) for Rho‐GTPases and convert GTP‐bound active form to GDP‐bound inactive form. However, no such effector molecule has been identified in Mycobacterium tuberculosis. In this study, we show that culture supernatant of M. tuberculosis H₃₇Rv harbors a protein that stimulates the conversion of GTP‐bound Rho‐GTPases to the GDP‐bound form. Nucleoside diphosphate kinase (Ndk) was identified as this culture supernatant protein that stimulated in vitro GTP hydrolysis by members of Rho‐GTPases. The histidine‐117 mutant of Ndk, which is impaired for autophosphorylation and nucleotide‐binding activities, shows GAP activity. These results suggest that Ndk of M. tuberculosis functions as a Rho‐GAP to downregulate Rho‐GTPases, and this activity may aid in pathogenesis of the bacteria.