Localization and Function of Bacterial Type III and IV Effector Proteins




Jimenez, Alyssa

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Eukaryotic cell signal transduction networks are highly dynamic and complex systems largely composed of signaling enzymes with modular protein interaction domains and subcellular localization motifs. These sophisticated regulatory mechanisms are crucial to the fidelity and efficacy of information relay in both space and time. Bacterial effector proteins are virulence factors that are directly secreted from the bacteria into the host cytosol and function to rewire eukaryotic signaling networks to establish an environment for bacterial survival. While much effort has gone into substrate identification and biochemical characterization of bacterial effector proteins, it remains unclear how these bacterial enzymes are able to amplify their signaling events to efficiently usurp the robust signaling networks of eukaryotic cells. To this end, I utilized a yeast genetic screen to ask whether bacterial effectors proteins are able to interact with eukaryotic membranes, structures that serve as organizational platforms for the assembly of multi-protein complexes critical for eukaryotic signal transduction. By focusing on a family of bacterial guanine nucleotide exchange factors (GEFs) that activate Rho-family GTPases, and are indispensable for the characteristic accumulation of actin at the site of bacterial attachment and invasion, I have identified a membrane-localization domain in the Salmonella effectors SopE and SopE2 that regulates the ability of these effectors to activate Rho GTPases and invade eukaryotic cells. This membrane-localization domain may function to concentrate these effectors to the highly curved membranes found during Salmonella invasion. Additionally, a polybasic domain identified in the Shigella GEF IpgB1 was found to spatially and temporally regulate actin dynamics. Furthermore, the subcellular location of previously uncharacterized Legionella effectors were found to localize to the vacuoles in yeast and may play a role in regulating vacuolar fusion. Lastly, to gain a greater comprehension of the complex interplay of Salmonella SPI-2 effectors, I developed a collection of Salmonella mutant strains consisting of single SPI-2 effector deletions and a series of combinatorial mutants that are deficient in 2 to 29 effectors. This study expands our knowledge on fundamental processes critical to host-pathogen interactions and provides important mechanistic insights into the spatiotemporal regulation of bacterial effector proteins.

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