Protein acyltransferase mediated S-palmitoylation and its Importance in Innate Immunity and Lipid Metabolism.

Most of the essential processes within our cells are carried out by molecules called 'proteins'. Proteins are made from a specific combination of building blocks termed amino acids. In the simplest case, proteins are a combination of the standard 20 amino acid alphabet. However, to achieve enhanced diversity beyond the 20 amino acids, some of these building blocks can be chemically modified. These modifications can act as an 'on-off' switch, a signal to control protein localization or as a way of marking old proteins for recycling. The goal of this proposal is to understand a poorly studied modification termed S-palmitoylation. This modification involves attaching a 16 carbon long fat to a particular amino acid. Because 16 carbon fats are hydrophobic (doesn't like being in water) this modification can target proteins to cellular compartments delineated by other fatty molecules. The human cells contain 24 enzymes that perform this modification yet little is known about these enzymes, and only a few of their targets have been identified. We have found that one of these enzymes modifies proteins critical for detecting bacteria and alerting the immune system. We have found that patients with defects in this chemical modification are prone to disorders such as Crohn's disease. In another example, we find that S-palmitoylation is critical for the liver to metabolize fats and defects may cause fatty liver disease and liver cancer. Overall, the primary outcome of this grant will be to characterize these new targets of S-palmitoylation and identify the enzymes responsible for the modification. We will also gain insight into how this modification impacts the localization and function of proteins essential for the immune system and in metabolism. Understanding this level of regulation within the cell may allow for the development of treatments to reverse or bypass the defects seen in patients with these specific immune disorders and fatty liver disease or liver cancer.