Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH, USA.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy at The Ohio State University, Columbus, OH, USA.
Nat Metab. 2022 May;4(5):575-588. doi: 10.1038/s42255-022-00568-y. Epub 2022 May 9.
Tumorigenesis is associated with elevated glucose and glutamine consumption, but how cancer cells can sense their levels to activate lipid synthesis is unknown. Here, we reveal that ammonia, released from glutamine, promotes lipogenesis via activation of sterol regulatory element-binding proteins (SREBPs), endoplasmic reticulum-bound transcription factors that play a central role in lipid metabolism. Ammonia activates the dissociation of glucose-regulated, N-glycosylated SREBP-cleavage-activating protein (SCAP) from insulin-inducible gene protein (Insig), an endoplasmic reticulum-retention protein, leading to SREBP translocation and lipogenic gene expression. Notably, 25-hydroxycholesterol blocks ammonia to access its binding site on SCAP. Mutating aspartate D428 to alanine prevents ammonia binding to SCAP, abolishes SREBP-1 activation and suppresses tumour growth. Our study characterizes the unknown role, opposite to sterols, of ammonia as a key activator that stimulates SCAP-Insig dissociation and SREBP-1 activation to promote tumour growth and demonstrates that SCAP is a critical sensor of glutamine, glucose and sterol levels to precisely control lipid synthesis.
肿瘤发生与葡萄糖和谷氨酰胺消耗的增加有关，但癌细胞如何感知其水平以激活脂质合成尚不清楚。在这里，我们揭示了来自谷氨酰胺的氨通过激活固醇调节元件结合蛋白（SREBPs）促进脂肪生成，SREBPs 是内质网结合的转录因子，在脂质代谢中发挥核心作用。氨激活了葡萄糖调节的、N-糖基化 SREBP 切割激活蛋白（SCAP）与胰岛素诱导基因蛋白（Insig）的解离，Insig 是一种内质网保留蛋白，导致 SREBP 易位和脂肪生成基因表达。值得注意的是，25-羟基胆固醇阻止氨进入其在 SCAP 上的结合位点。将天冬氨酸 D428 突变为丙氨酸可防止氨与 SCAP 结合，从而消除 SREBP-1 的激活并抑制肿瘤生长。我们的研究描述了氨作为一种关键激活剂的未知作用（与固醇相反），它刺激 SCAP-Insig 解离和 SREBP-1 激活，以促进肿瘤生长，并证明 SCAP 是谷氨酰胺、葡萄糖和固醇水平的关键传感器，可精确控制脂质合成。
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