CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4.
CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4.
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DOI：
10.1016/j.molcel.2019.01.037
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发表时间：
2019-04
期刊：
影响因子：
16
通讯作者：
Xiphias Ge Zhu;Shirony Nicholson Puthenveedu;Yihui Shen;Konnor C. La;C. Ozlu;Tim Wang;Diana Klompstra;Yetis Gultekin;Jingyi Chi;Justine Fidelin;Tao Peng;H. Molina;H. Hang;Wei Min;Kıvanç Birsoy
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文献类型：
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作者：
Xiphias Ge Zhu;Shirony Nicholson Puthenveedu;Yihui Shen;Konnor C. La;C. Ozlu;Tim Wang;Diana Klompstra;Yetis Gultekin;Jingyi Chi;Justine Fidelin;Tao Peng;H. Molina;H. Hang;Wei Min;Kıvanç Birsoy
细胞需要不断供应脂肪酸才能生存和增殖。脂肪酸通过一系列内质网（ER）酶进入膜和储存甘油脂，但这些酶是如何调节的还不清楚。在这里，使用基于CRISPR的遗传筛选和无偏脂质组学的组合，我们确定钙调磷酸酶B同源蛋白1（CHP 1）是ER甘油酯合成的主要调节因子。CHP 1的缺失严重降低了哺乳动物细胞和无脊椎动物中脂肪酸的掺入和储存。在机制上，CHP 1结合并激活GPAT 4，其催化甘油脂质合成中的初始限速步骤。GPAT 4活性需要CHP 1被N-肉豆蔻酰化，在两种蛋白质之间形成关键的分子界面。有趣的是，在CHP 1损失时，过氧化物酶体酶GNPAT部分补偿ER脂质合成的损失，从而使细胞增殖。因此，我们的工作确定了一个保守的调节甘油脂质代谢，并揭示了可塑性的脂质合成的增殖细胞。
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.