Cell and organelle membranes consist of a complex mixture of phospholipids (PLs) that determine their size, shape, and function. Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes, yet how cells sense and regulate its levels in vivo remains unclear. Here we show that PCYT1A, the rate-limiting enzyme of PC synthesis, is intranuclear and re-locates to the nuclear membrane in response to the need for membrane PL synthesis in yeast, fly, and mammalian cells. By aligning imaging with lipidomic analysis and data-driven modeling, we demonstrate that yeast PCYT1A membrane association correlates with membrane stored curvature elastic stress estimates. Furthermore, this process occurs inside the nucleus, although nuclear localization signal mutants can compensate for the loss of endogenous PCYT1A in yeast and in fly photoreceptors. These data suggest an ancient mechanism by which nucleoplasmic PCYT1A senses surface PL packing defects on the inner nuclear membrane to control PC homeostasis.

细胞和细胞器膜由磷脂 (PL) 的复杂混合物组成，决定了它们的大小、形状和功能。磷脂酰胆碱（PC）是真核细胞膜中最丰富的磷脂，但细胞在体内如何感知和调节其水平仍不清楚。在这里，我们发现 PCYT1A（PC 合成的限速酶）位于核内，并重新定位到核膜，以响应酵母、果蝇和哺乳动物细胞中膜 PL 合成的需要。通过将成像与脂质组学分析和数据驱动建模相结合，我们证明酵母 PCYT1A 膜关联与膜存储的曲率弹性应力估计相关。此外，尽管核定位信号突变体可以补偿酵母和果蝇光感受器中内源性 PCYT1A 的损失，但该过程发生在细胞核内部。这些数据表明了一种古老的机制，核质 PCYT1A 通过感知内核膜上的表面 PL 堆积缺陷来控制 PC 稳态。