CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4
| Autor: | Henrik Molina, Wei Min, Jingyi Chi, Yetis Gultekin, Yihui Shen, Tao Peng, Justine Fidelin, Timothy C. Wang, Shirony Nicholson Puthenveedu, Xiphias Ge Zhu, Konnor La, Can Ozlu, Howard C. Hang, Kıvanç Birsoy, Diana Klompstra |
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| Rok vydání: | 2019 |
| Předmět: |
Palmitic Acid
Regulator Biology Endoplasmic Reticulum Article Gene Expression Regulation Enzymologic Glycerides Jurkat Cells Mice 03 medical and health sciences 0302 clinical medicine Lipidomics Animals Drosophila Proteins Humans Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology Cell Proliferation 030304 developmental biology chemistry.chemical_classification 0303 health sciences Cell growth Lipogenesis Endoplasmic reticulum Calcium-Binding Proteins Fatty acid Lipid metabolism 3T3 Cells Hep G2 Cells Cell Biology Cell biology Enzyme Activation Drosophila melanogaster HEK293 Cells Enzyme chemistry Glycerol-3-Phosphate O-Acyltransferase Acyltransferases 030217 neurology & neurosurgery HeLa Cells Protein Binding Genetic screen |
| Zdroj: | Molecular Cell. 74:45-58.e7 |
| ISSN: | 1097-2765 |
| Popis: | Summary Cells require a constant supply of fatty acids to survive and proliferate. Fatty acids incorporate into membrane and storage glycerolipids through a series of endoplasmic reticulum (ER) enzymes, but how these enzymes are regulated is not well understood. Here, using a combination of CRISPR-based genetic screens and unbiased lipidomics, we identified calcineurin B homologous protein 1 (CHP1) as a major regulator of ER glycerolipid synthesis. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates. Mechanistically, CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis. GPAT4 activity requires CHP1 to be N-myristoylated, forming a key molecular interface between the two proteins. Interestingly, upon CHP1 loss, the peroxisomal enzyme, GNPAT, partially compensates for the loss of ER lipid synthesis, enabling cell proliferation. Thus, our work identifies a conserved regulator of glycerolipid metabolism and reveals plasticity in lipid synthesis of proliferating cells. |
| Databáze: | OpenAIRE |
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