Nuclear Pct1 couples phosphatidylcholine synthesis with membrane biogenesis

Abstract

Phosphatidylcholine (PC) is the major eukaryotic phospholipid and its synthesis must be homeostatically controlled to prevent excess membrane and organelle growth. Here we investigate how PC synthesis by the Kennedy pathway is coordinated with membrane biogenesis. In budding yeast, the rate-limiting enzyme Pct1 is nuclear and reversibly associates with the inner nuclear membrane (INM) in response to lipid packing defects caused by low PC. We show that the enzymes acting after Pct1 to generate PC remain at the endoplasmic reticulum (ER) during pathway activation. Relocating the final PC synthesis step to different endomembrane sites does not alter the kinetics of Pct1 release from the INM, indicating that newly made PC equilibrates with the INM rapidly. In contrast, elevated phosphatidic acid locks Pct1 at the INM, prevents pathway inactivation and drives nuclear/ER membrane proliferation. These results support a model in which nuclear Pct1 senses lipid imbalance while ER-localized enzymes supply PC; disrupting this homeostasis leads to uncontrolled membrane biogenesis.