Partitioning of fatty acids between membrane and storage lipids controls ER membrane expansion

Biogenesis of membrane-bound organelles involves the synthesis, remodelling, and degradation of their constituent phospholipids. How these pathways regulate organelle size remains poorly understood. Here we demonstrate that a lipid-degradation pathway inhibits expansion of the endoplasmic reticulum (ER) membrane. Phospholipid diacylglycerol acyltransferases (PDATs) use endogenous phospholipids as fatty-acyl donors to generate triglyceride stored in lipid droplets. The significance of this non-canonical triglyceride biosynthesis pathway has remained elusive. We find that the activity of the yeast PDAT Lro1 is regulated by a membrane-proximal helical segment facing the luminal side of the ER bilayer. To reveal the biological roles of PDATs, we engineered an Lro1 variant with derepressed activity. We show that active Lro1 mediates retraction of ER membrane expansion driven by phospholipid synthesis. Furthermore, subcellular distribution and membrane turnover activity of Lro1 are controlled by diacylglycerol produced by the activity of Pah1, a conserved member of the lipin family. Collectively, our findings reveal a lipid-metabolic network that regulates endoplasmic-reticulum biogenesis by converting phospholipids into storage lipids.

膜结合细胞器（membrane-bound organelles）的生物发生过程，涉及组成其膜结构的磷脂的合成、重塑与降解。目前学界对这些通路如何调控细胞器尺寸的机制仍知之甚少。本研究证实，一条脂质降解通路可抑制内质网（endoplasmic reticulum, ER）膜的扩张。磷脂二酰甘油酰基转移酶（phospholipid diacylglycerol acyltransferases, PDATs）以内源性磷脂作为脂肪酰基供体，合成储存于脂滴（lipid droplets）中的甘油三酯（triglyceride）。这一非经典甘油三酯生物合成通路的生物学意义此前尚未明确。我们发现，酵母PDAT Lro1的酶活受到一段面向ER双层膜腔侧的膜近端螺旋区段（membrane-proximal helical segment）的调控。为揭示PDATs的生物学功能，我们构建了活性解除抑制的Lro1突变体。研究表明，活化的Lro1可介导由磷脂合成驱动的ER膜扩张回缩。此外，Lro1的亚细胞分布与膜周转活性，受到Pah1——脂素家族（lipin family）的保守成员——所产生的二酰甘油（diacylglycerol）的调控。综上，本研究揭示了一条通过将磷脂转化为储存脂质来调控内质网生物发生的脂质代谢网络（lipid-metabolic network）。