Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions
| Autor: | H. Alex Brown, Mira Sohn, Pavlina T. Ivanova, Daniel J Toth, Péter Várnai, Tamas Balla, Yeun Ju Kim |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Phosphatidylinositol 4-phosphate Nitrogenous Group Transferases Phosphatase Mutant Golgi Apparatus Endoplasmic Reticulum Minor Histocompatibility Antigens 03 medical and health sciences symbols.namesake chemistry.chemical_compound Phosphatidylinositol Phosphates Intellectual Disability Humans Abnormalities Multiple Phosphatidylinositol chemistry.chemical_classification Bone Diseases Developmental Multidisciplinary ATP synthase biology Cell Membrane Golgi apparatus Biological Sciences Cell biology Phosphotransferases (Alcohol Group Acceptor) 030104 developmental biology Enzyme HEK293 Cells chemistry Biochemistry Mutation symbols biology.protein PI4KA |
| Popis: | Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in thePTDSS1gene 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. |
| Databáze: | OpenAIRE |
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