Elucidating the Secreted Bacterial Kinome




Lopez, Victor Antonio

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In the post-genomic era, millions of amino acid sequences have been acquired and revealed a remarkable diversity among protein families. This is especially apparent in pathogenic species where host and pathogen participate in an intense evolutionary arms race, and horizontal gene transfer is common. We have taken a bioinformatic approach to identify and characterize distant members of the protein kinase superfamily that share little sequence similarity, yet retain a kinase fold, and possibly catalytic activity. Using this approach, we identified the uncharacterized HopBF1and MavQ families of bacterial type III and type IV secretion system effectors, respectively, as remote members of the eukaryotic protein kinase superfamily. We demonstrate that the HopBF1 kinases are eukaryotic-specific HSP90 kinases. HopBF1 phosphorylates HSP90 on a strictly conserved serine that potently inactivates its ATPase activity, and inactivation by phosphorylation prevents the maturation or folding of various HSP90 clients, including immune receptors necessary for the activation of the hypersensitive response in plants. Consequently, HopBF1 kinase activity is sufficient to induce severe disease symptoms in plants infected with the bacterial plant pathogen, Pseudomonas syringae. Moreover, we show that MavQ is a phosphatidylinositol (PI) 3-kinase required for full Legionella virulence in a eukaryotic host. MavQ and the Legionella PI 3-phosphatase SidP drive rapid PI 3-phosphate turnover on the ER and spontaneously form traveling waves that spread along ER subdomains and induce vesicle/tubule budding. Our results reveal a novel mechanism by which self-organizing bacterial effectors remodel host cellular membranes for survival and uncover a family of bacterial effector kinases which act to compromise the host immune response through a "betrayal-like" mechanism.

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Pages vi-x are misnumbered as pages v-ix.

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