Spatial regulation of phospholipid synthesis within the nuclear envelope domain of the endoplasmic reticulum

The endoplasmic reticulum (ER) is an extensive membrane system that serves as a platform for de novo phospholipid synthesis. The ER is partitioned into distinct functional and structural domains, the most notable of which is the nuclear envelope. Here we discuss the role of nuclear envelope localized CNEP-1(Nem1) in spatial regulation of de novo phospholipid synthesis within the ER. CNEP-1(Nem1) is an activator of lipin(Pah1), which is the key phosphatidic acid phosphatase that regulates the metabolic branch-point between the production of phosphatidylinositol (PtdIns) and major membrane phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE). CNEP-1 activates lipin at the nuclear envelope to bias phospholipid flux toward PC and PE production and to limit PtdIns incorporation. Increased PtdIns causes the formation of ectopic ER sheets in the vicinity of the nucleus that wrap around the nuclear envelope and cause downstream defects in NE disassembly. We propose that spatial regulation of phospholipid flux promotes partitioning of the ER into distinct sub-domains by generating a gradient of PtdIns incorporation.