Ice2 promotes ER membrane biogenesis in yeast by inhibiting the conserved lipin phosphatase complex

Cells dynamically adapt organelle size to current physiological demand. Organelle growth requires membrane biogenesis and therefore needs to be coordinated with lipid metabolism. The endoplasmic reticulum (ER) can undergo massive expansion, but the underlying regulatory mechanisms are largely unclear. Here, we describe a genetic screen for factors involved in ER membrane expansion in budding yeast and identify the ER transmembrane protein Ice2 as a strong hit. We show that Ice2 promotes ER membrane biogenesis by opposing the phosphatidic acid phosphatase Pah1, called lipin in metazoa. Specifically, Ice2 inhibits the conserved Nem1‐Spo7 complex and thus suppresses the dephosphorylation and activation of Pah1. Furthermore, Ice2 cooperates with the transcriptional regulation of lipid synthesis genes and helps to maintain cell homeostasis during ER stress. These findings establish the control of the lipin phosphatase complex as an important mechanism for regulating ER membrane biogenesis. Synopsis Organelle biogenesis typically requires synthesis of new membrane and thus depends on lipid metabolism. A genetic screen identifies the ER protein Ice2 as a regulator of lipid metabolism and a major factor for ER membrane biogenesis. Ice2 regulates lipid metabolism and promotes ER membrane biogenesis through inhibition of the phosphatidic acid phosphatase Pah1/lipin Ice2 opposes Pah1 activation by interacting with and restraining the Nem1‐Spo7 phosphatase complex Ice2 cooperates with the transcriptional regulators of lipid metabolism Opi1‐Ino2/4 to control ER membrane biogenesis Ice2 regulation of lipid metabolism helps to maintain ER homeostasis and supports cell growth, particularly during ER stress Graphical Abstract A screen for factors involved in ER membrane expansion identifies a role for ER transmembrane protein Ice2 via inhibition of the Nem1‐Spo7/Pah1‐lipin phosphatase cascade.