The mTOR-Dop1a-Agpat2 axis regulates nuclear phospholipid homeostasis.

The molecular mechanisms regulating the phospholipid (PL) metabolism in the nucleus remain to be elucidated. Here, we describe the role of Dop1a in controlling PL abundance in nuclear membranes (NMs) under the control of mTOR signaling. A shortage of lysophosphatidic acid (LPA) triggers the rapid localization of Dop1a to the nuclear pore complexes (NPCs), where Dop1a suppresses PL synthesis by binding to AGPAT2 (1-acylglycerol-3-phosphate O-acyltransferase 2), which is also localized at the NPCs. Loss of Dop1a results in elevated PL production, which leads to the formation of nuclear lipid droplets (nLDs). The titration of PL abundance is coordinated with proper cell cycle entry by Dop1a that restricts nuclear accumulation of CDK2. Thus, Dop1a safeguards cell division via surveilling the PL supply. Dop1a is highly expressed in neurons and is essential for neurobehavioral development in mice. DOP1A mutations have been identified in patients with neurodevelopmental disorders (NDDs). Thus, the proper function of Dop1a is crucial for the proper development of the nervous system.