Role of E3 ubiquitin ligase in Salmonella-induced inflammation

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DESCRIPTION (provided by applicant): Salmonellosis continues to pose worldwide medical concerns and remains the number one cause of foodborne diseases in humans and animals. SopA was identified as an SPI-1 effector and has been shown to be translocated into the host cells and to play a key role in PMN trans-epithelial migration and the induction of enteritis. The molecular and biochemical mechanisms by which Salmonella and SopA induce intestinal inflammation and enteritis are not understood. We have recently found that SopA interacts with human RMA1 (HsRMA1), an E3 ubiquitin ligase. Surprisingly, we also discovered that SopA itself is an E3 ubiquitin ligase, suggesting SopA must ubiquitinate bacterial and/or host cellular substrates to exert its function in Salmonella-induced enteritis. The identification of the Salmonella E3 ubiquitin ligase, SopA, has provided us with a unique tool to study SopA function and to help unravel the molecular and biochemical mechanisms by which Salmonella and SopA induce intestinal inflammation and enteritis. My working hypothesis is that a coordinated strategy is employed by Salmonella to inject bacterial proteins into the host cells and to program their destruction by exploiting the host ubiquitination pathways in order to facilitate bacterial survival while reducing prolonged adverse effects on the host cells exerted by these bacterial effectors. Thus, the goal of this project is to characterize SopA and its E3 ubiquitin ligase activity in Salmonella-induced intestinal inflammation and enteritis, using genetic, biochemical and cell biological approaches. We propose to: 1) examine roles of Salmonella SopA and its E3 ubiquitin ligase activity in chemokine induction and neutrophile migration; 2) identify and characterize bacterial and host proteins that are substrates for the host HsRMA1 and Salmonella SopA. These studies will help us to understand the molecular mechanism by which Salmonella induces intestinal inflammation and enteritis. Results from this study will contribute to the emerging field of cellular microbiology and to the field of cell biology, especially the regulation of ubiquitination in host cells. An award would significantly reduce my teaching and service obligations within the Department. My research involves a broad scope of both cell biology and microbiology. It requires constant update of the background knowledge and techniques needed for these projects. A K02 award will allow me to spend more time on my research and greatly enhance my research career. My department is committed to a strong research program in this area and has provided an excellent environment to carry out my research goals.