Control of organelle biogenesis by the Lipin switch
Cells dynamically adjust the biogenesis of their organelles to physiological demand. Particularly striking examples of this phenomenon are the biogenesis of the endoplasmic reticulum (ER) and lipid droplets (LDs), as cells can change the sizes of these organelles by several fold. Organelle biogenesis requires lipids for the production of new membranes and hence needs to be coordinated with lipid metabolism. An important regulator of lipid metabolism is Lipin, a conserved molecular switch that catalyzes the conversion of phosphatidic acid into diacylglycerol and additionally controls the transcription of lipid metabolism genes. The activity of Lipin depends on its reversible relocation from the cytosol to the ER membrane and the nucleus, which, in turn, is governed by the phosphorylation status of Lipin. However, despite substantial recent progress, the exact function of Lipin in organelle biogenesis has remained unclear.
In the last funding period, the Schuck lab concluded a study that uncovered a new regulator of the Lipin phosphatase complex in yeast and identified yeast Lipin as a crucial element of ER size control. We then investigated Lipin function in human cells and showed its importance for both ER and LD biogenesis. In addition, we found that ER stress increases Lipin activity, implying that Lipin may drive ER membrane expansion upon activation of the unfolded protein response. The Daumke lab developed purification protocols for constructs of the three human Lipins and established a biochemical phosphatase assay to measure their catalytic activities. With these tools, we carried out a small-molecule screen and identified a panel of inhibitors that target either only Lipin-2 or all three Lipins at once. Together, the Daumke and Schuck labs then showed that some of these inhibitors affect ER biogenesis and lipid storage in human cells.
In the coming funding period, we will employ structure-based drug design to improve the affinity and specificity of the Lipin inhibitors and develop them as chemical tools to study and manipulate the cellular functions of the Lipin switch. Furthermore, we will continue to investigate how Lipin controls ER and LD biogenesis in human cells. For this, we will define the contributions of the lipid phosphatase and transcriptional regulator activities of Lipin to organelle biogenesis and explore the spatial organization of the Lipin switch, including its oligomerization, mechanism of membrane association and distribution within the ER network. Our work will shed light on a major molecular switch in the regulation of lipid metabolism and organelle biogenesis. In addition, it may yield compounds that hold promise for treating diseases associated with dysregulated lipid metabolism, such as obesity, fatty liver disease and cancer.
Dr. Sebastian Schuck (ZMBH)
Prof. Dr. Oliver Daumke (MDC Berlin)