Lenz Majewski mutations in PTDSS1 affect phosphatidylinositol 4 phosphate metabolism at ER PM and ER Golgi junctions
Significance Phosphatidylserine (PS) is synthesized in the endoplasmic reticulum by PS synthase enzymes, but most of the PS is found in the inner leaflet of the plasma membrane. The importance of the present findings is that they uncover a critical connection between PI4P turnover and PS transport and demonstrate that uncontrolled PS synthesis as seen in Lenz Majewski syndrome patients has deleterious consequences to cells affecting other lipids and not just PS. Lenz Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in the PTDSS1 gene coding one of the phosphatidylserine (PS) synthase enzymes, PSS1, were described as causative in LMS patients. Such mutations render PSS1 insensitive to feedback inhibition by PS levels. Here we show that expression of mutant PSS1 enzymes decreased phosphatidylinositol 4 phosphate (PI4P) levels both in the Golgi and the plasma membrane (PM) by activating the Sac1 phosphatase and altered PI4P cycling at the PM. Conversely, inhibitors of PI4KA, the enzyme that makes PI4P in the PM, blocked PS synthesis and reduced PS levels by 50% in normal cells. However, mutant PSS1 enzymes alleviated the PI4P dependence of PS synthesis. Oxysterol binding protein related protein 8, which was recently identified as a PI4P PS exchanger between the ER and PM, showed PI4P dependent membrane association that was significantly decreased by expression of PSS1 mutant enzymes. Our studies reveal that PS synthesis is tightly coupled to PI4P dependent PS transport from the ER. Consequently, PSS1 mutations not only affect cellular PS levels and distribution but also lead to a more complex imbalance in lipid homeostasis by disturbing PI4P metabolism.
Proceedings of the National Academy of Sciences