Control of endoplasmic reticulum membrane biogenesis by regulators of lipid metabolism

Cells dynamically adapt organelle size to current physiological demand. Organelle growth and proliferation require membrane biogenesis and need to be coordinated with lipid metabolism. The endoplasmic reticulum (ER) can undergo massive expansion but the mechanisms that govern ER membrane biogenesis are unclear. Here, we genetically screen for factors mediating ER expansion in budding yeast and identify lipid synthesis enzymes and the ER transmembrane protein Ice2 as strong hits. Ice2 inhibits the conserved phosphatidic acid phosphatase Pah1 by opposing the activity of the Nem1-Spo7 complex. This regulation counteracts the production of storage lipids and directs lipid metabolism towards membrane biogenesis. Furthermore, Ice2 acts in concert with the transcriptional control of lipid synthesis enzymes and cooperates with the unfolded protein response to maintain ER homeostasis. These findings establish the regulation of the lipin ortholog Pah1 as a key determinant of ER membrane biogenesis.