Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Nat Commun. 2024 Mar 18;15(1):2441. doi: 10.1038/s41467-024-46696-9.
Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.
在细胞周期中，脂质合成会增加以确保有足够的膜质量，但人们尚不清楚脂质合成不足如何限制细胞周期进入。在这里，我们通过对非转化细胞进行活细胞单颗粒成像、脂质组学和转录组学分析，鉴定出哺乳动物细胞周期 G1 期的脂质检查点。我们表明，G1 期脂肪酸的合成不仅增加了脂质质量，而且还广泛地将脂质组成转移到不饱和磷脂和中性脂质。引人注目的是，急性降低脂质合成会迅速激活 PERK/ATF4 内质网 (ER) 应激途径，该途径通过增加 p21 水平、降低 Cyclin D 水平和抑制视网膜母细胞瘤蛋白磷酸化来阻止细胞周期进入。总之，我们的研究在 G1 期鉴定出一个快速的 ER 脂质检查点，只要脂质合成低，它就会阻止细胞开始细胞周期，从而防止由后期有丝分裂中低脂质合成引发的有丝分裂缺陷。
