Lysyganicz Pawel K, Barbosa Antonio D, Khondker Shoily, Stewart Nicolas A, Carman George M, Stansfeld Phillip J, Dymond Marcus K, Siniossoglou Symeon
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
Department of Food Science and the Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, 08901, USA.
EMBO J. 2025 Feb;44(3):781-800. doi: 10.1038/s44318-024-00355-3. Epub 2025 Jan 3.
Biogenesis of membrane-bound organelles involves the synthesis, remodeling, 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.
膜结合细胞器的生物发生涉及其组成磷脂的合成、重塑和降解。这些途径如何调节细胞器大小仍知之甚少。在这里，我们证明了一种脂质降解途径会抑制内质网（ER）膜的扩张。磷脂二酰甘油酰基转移酶（PDATs）利用内源性磷脂作为脂肪酰供体来生成储存在脂滴中的甘油三酯。这种非经典甘油三酯生物合成途径的意义一直难以捉摸。我们发现酵母PDAT Lro1的活性受面向ER双层腔侧的膜近端螺旋段调控。为了揭示PDATs的生物学作用，我们构建了一种活性去抑制的Lro1变体。我们表明，有活性的Lro1介导由磷脂合成驱动的ER膜扩张的回缩。此外，Lro1的亚细胞分布和膜周转活性由脂素家族保守成员Pah1的活性产生的二酰甘油控制。总的来说，我们的研究结果揭示了一个通过将磷脂转化为储存脂质来调节内质网生物发生的脂质代谢网络。
