In recent years, modulation of the sphingolipid metabolism has emerged as key step in the regulation of signal transduction in eukaryotic organisms and in the development of pathobiological disorders. Cryptococcus neoformans is an opportunistic pathogen that commonly infects AIDS patients and also can infect transplant recipients and cancer patients. This application proposes a crucial role for the sphingolipid metabolism in the pathobiological process caused by C. neoformans, focusing on inositol-phosphoryl ceramide synthase 1 (Ipc1), which catalyzes the first fungal-specific step of the sphingolipid biosynthesis. Despite the importance of this key enzyme, little is known about its mechanisms of action with respect to pathogenicity. Recent studies in the laboratory of the PI have shown that Ipc1 regulates the infectivity C. neoformans through the modulation of melanin production, a well-established virulence factor, required by the pathogen to produce disease. In mammalian models, melanogenesis is regulated by activation of protein kinase C (PKC) through a diacylglycerol (DAG)-dependent manner. Since the Ipc1 reaction also leads to the formation of DAG and block of Pkc1 (fungal homolog of mammalian PKC) significantly reduces melanin formation of C. neoformans, we HYPOTHESIZE that Ipc1 is a key regulator of pathogenicity of C. neoformans in part by affecting melanin production through the formation of DAG and the consequent activation of Pkc1. Therefore we will: 1) determine the role and mechanism by which Ipc1 regulates Pkc1; and 2) establish the role and mechanism by which Pkc1 regulates melanin formation. Significance. These studies will provide significant insights into novel mechanisms for sphingolipids and DAG for the regulation of the fungal pathogenicity, and they will also allow the characterization of novel targets, such as Ipc1 and Pkc1, for the development of new antifungal drugs.
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