Exploring the Dynamics and Regulatory Functions of Nuclear Lipids

Abstract

Phospholipid composition of biological membranes is critical for the control of numerous cellular processes in eukaryotic cells. Much less is known about the role of the nuclear phospholipids in the control of nuclear functions. Recently, biosensors with higher sensitivity and specificity, have been successfully used to follow the cellular distribution and dynamic changes of selected lipids in living cells. These included sensors for various phosphoinositides (PPIns), diacylglycerol (DAG), phosphatidic acid (PA), phosphatidylserine (PS) and cholesterol (Cho). To explore the importance of nuclear phospholipids in the control of different cellular processes, we set out to assess their presence and distribution in the nucleus both in steady state and in response to environmental challenges. For this, we created versions of the lipid sensors that allow probing lipid distribution and changes within the nucleus. Using these tools, we observed the enrichment of PS and DAG in the inner nuclear membrane (INM) in steady state and found that both PS and DAG showed characteristic changes in response to metabolic challenges, such as fatty acid loading or nutrient deprivation. These changes prompted us to seek nuclear proteins that respond to and are controlled by these lipid changes. In addition, we also created cell lines with stable and inducible expression of the biosensors to follow the dynamic changes in those lipids both within and outside of the nucleus during the cell cycle. Since such sensors may interfere with the biology regulated by these lipids, it was critical to allow for their controlled expression. These experiments are still in progress and we will share our newest data obtained by these ongoing efforts. We believe our data will shed important new light on the regulatory changes in phospholipids within the inner nuclear membrane and on their importance in the control of nuclear processes.