Sci. Signal., 11 September 2012
Cell Biology Bacterial Traffic Jammers
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
Members of the Rab family of guanosine triphosphatases (GTPases) regulate various aspects of vesicular trafficking. When bound to guanosine triphosphate (GTP), Rab GTPases become activated, and hydrolysis of GTP to GDP renders Rab proteins inactive. Rab activity is promoted by guanine nucleotide exchange factors, whereas Rab inactivation is stimulated by GTPase-activating proteins (GAPs), which have a catalytic TBC domain that contains an "arginine finger" that catalyzes GTP hydrolysis. Because of their roles in regulating vesicular trafficking, Rab proteins are often targeted by bacterial pathogens that reside in vesicular compartments in infected cells. Dong et al. found that two secreted bacterial effector proteins, VirA from Shigella flexneri, which replicates in the cytoplasm, and EspG from the pathogen Enteropathogenic Escherichia coli (EPEC), had some amino acid sequence similarity to the arginine finger. In vitro studies showed that VirA and EspG preferentially inhibited Rab1. Inactivation of Rab1 in cells expressing VirA disrupted trafficking from the endoplasmic reticulum (ER) to the Golgi, and this effect depended on residues critical for the arginine finger motif. Analysis of complexes of VirA or EspG bound to Rab1 showed that the bacterial proteins had no substantial structural similarity with the TBC domain of an endogenous Rab GAP, except for the arginine finger region. In the case of S. flexneri, inactivation of Rab1 by VirA blocked the autophagy-dependent host defense response of the infected cells, enabling the pathogen to survive. For EPEC, EspG-mediated inactivation of Rab1 prevented the secretion by the infected cells of the chemokine IL-8, which is required for the host response. Together, these data suggest that pathogens that are not sequestered in a vesicular compartment produce effector proteins that act as Rab GAPs to disrupt different aspects of the host response to their advantage.
N. Dong, Y. Zhu, Q. Lu, L. Hu, Y. Zheng, F. Shao, Structurally distinct bacterial TBC-like GAPs link Arf GTPase to Rab1 inactivation to counteract host defenses. Cell 150, 1029–1041 (2012). [PubMed]
Citation: J. F. Foley, Bacterial Traffic Jammers. Sci. Signal. 5, ec240 (2012).
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