当前位置: X-MOL 学术Nat. Metab. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth
Nature Metabolism ( IF 18.9 ) Pub Date : 2022-05-09 , DOI: 10.1038/s42255-022-00568-y
Chunming Cheng 1 , Feng Geng 1 , Zoe Li 2 , Yaogang Zhong 1 , Huabao Wang 1 , Xiang Cheng 1 , Yue Zhao 3 , Xiaokui Mo 4 , Craig Horbinski 5 , Wenrui Duan 6 , Arnab Chakravarti 1 , Xiaolin Cheng 2, 7 , Deliang Guo 1, 8
Affiliation  

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.



中文翻译:

氨刺激 SCAP/Insig 解离和 SREBP-1 激活,促进脂肪生成和肿瘤生长

肿瘤发生与葡萄糖和谷氨酰胺消耗升高有关,但癌细胞如何感知它们的水平以激活脂质合成尚不清楚。在这里,我们揭示了从谷氨酰胺释放的氨通过激活甾醇调节元件结合蛋白(SREBP)促进脂肪生成,SREBP是内质网结合的转录因子,在脂质代谢中发挥核心作用。氨激活葡萄糖调节的N-糖基化 SREBP 裂解激活蛋白 (SCAP) 从胰岛素诱导基因蛋白 (Insig)(一种内质网保留蛋白)的解离,导致 SREBP 易位和脂肪生成基因表达。值得注意的是,25-羟基胆固醇会阻止氨进入其在 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,消除 SREBP-1 激活并抑制肿瘤生长。我们的研究描述了与甾醇相反的氨作为关键激活剂的未知作用,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、葡萄糖和甾醇水平的关键传感器,可精确控制脂质合成。

更新日期:2022-05-10
down
wechat
bug