Investigating the mechanisms of phosphatidylcholine sensing

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Biological membranes are essential for all aspects of life; they separate the interior of cells from their environment; they organize the intracellular space into several compartments, or organelles, each with its own specific role; and they also function as platforms onto which complex chemical reactions take place. The basic building blocks of membranes are lipids. Therefore, it is critical that cells produce lipids at the right time and place. The amount and type of membrane lipids must be carefully controlled to match the specific requirements of each cell: for example, rapidly proliferating cells or cells expanding their intracellular organelles require more lipid synthesis to support the growth of the corresponding membranes. In this project we will investigate how cells monitor and adjust the levels of phosphatidylcholine (PC), the most abundant lipid in eukaryotic membranes.The enzyme that controls the rate of PC production is called CCTa. Because PC is a cylindrical lipid, its depletion disrupts proper lipid packing within the membrane; this is sensed by CCTa, which is then activated to correct the defect. We recently found that this process takes place inside the nucleus of many different eukaryotic cells: when inactive, CCTa is intranuclear, while when cells need to make more PC, the enzyme associates with the inner side of the nuclear membrane, which separates the nucleus from the cytoplasm. This finding is surprising given that lipid synthesis is mostly a cytoplasmic process. In the proposed work, we will determine how CCTa associates with the inner nuclear membrane, why this process is restricted within the nucleus and how it is coordinated with the final step of PC synthesis which takes place in the cytoplasm.Our recent work shows that the sensing of PC is highly conserved from simple unicellular organisms to humans. Therefore, we will carry out the initial discovery phase of our research in budding yeast as a model organism that provides rapid insights; in a second phase we will determine how these outcomes apply in human cells. We believe that this work will contribute to the understanding of a fundamental step in lipid metabolism and could guide future therapeutic approaches against lipid metabolic and visual disorders, which are caused by PC deficiency.