DIM

Project "DIM" data sheet

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 Project objective

The protein interferon stimulated gene 15 (ISG15) is a highly conserved ubiquitin-like modifier important for innate immune responses in mammals. ISG15 is highly abundant in cell lysates and enriched on the phagosome of interferon-activated macrophages. In humans, lack of ISG15 leads to increased susceptibility to infection by mycobacterial pathogens that reside in the phagosome of macrophages. However, both ISGylation events and their role are poorly characterized. This is partly due to the lack of analytical tools for the identification of ISGylation sites in cells. Here, I propose to develop a proteomics strategy to enrich and identify ISG15 targets that will also allow characterizing the interplay of ISG15 with ubiquitin. I will apply this method to analyze how ISGylation changes in response to Salmonella infection in macrophages. In order to understand the mechanisms that lead to susceptibility to intracellular pathogens, I will further use these approaches to test how ISGylation affects phagosome biogenesis in macrophages. ISG15 substrates identified in my proteomics screens will be validated and further characterized using biochemical, cell biological and immunological tools. Altogether, this data will provide new functional insights how ISG15 regulates defense mechanisms against bacterial infections.