Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth.
Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth.
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DOI：
10.1038/s42255-022-00568-y
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发表时间：
2022-05
影响因子：
20.8
通讯作者：
Guo, Deliang
中科院分区：
文献类型：
--
作者：
Cheng, Chunming;Geng, Feng;Li, Zoe;Zhong, Yaogang;Wang, Huabao;Cheng, Xiang;Zhao, Yue;Mo, Xiaokui;Horbinski, Craig;Duan, Wenrui;Chakravarti, Arnab;Cheng, Xiaolin;Guo, Deliang
肿瘤发生与葡萄糖和谷氨酰胺消耗量升高有关，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，我们揭示了氨，从谷氨酰胺释放，促进脂肪生成通过激活固醇调节元件结合蛋白（SREBPs），内质网（ER）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ER滞留蛋白Insig中解离，导致SREBP易位和脂肪生成基因表达。有趣的是，25-羟基胆固醇阻断氨进入其在SCAP上的结合位点。将天冬氨酸D428突变为丙氨酸阻止氨与SCAP结合，消除SREBP-1活化，并抑制肿瘤生长。我们的研究表征了氨作为刺激SCAP/Insig解离和SREBP-1活化以促进肿瘤生长的关键活化剂的未知作用，与甾醇相反，并证明SCAP是谷氨酰胺，葡萄糖和甾醇水平的关键传感器以精确控制脂质合成。
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 (ER)-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 Insig, an ER-retention protein, leading to SREBP translocation and lipogenic gene expression. Interestingly, 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 tumor 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 tumor growth, and demonstrates that SCAP is a critical sensor of glutamine, glucose and sterol levels to precisely control lipid synthesis.
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DOI：
10.1186/s40880-018-0301-4
发表时间：
2018-05-21
期刊：
Cancer communications (London, England)
影响因子：
--
作者：
Cheng C;Geng F;Cheng X;Guo D
通讯作者：
Guo D
影响因子：
29
作者：
Cheng, Xiang;Geng, Feng;Guo, Deliang
通讯作者：
Guo, Deliang
DOI：
10.1073/pnas.0500206102
发表时间：
2005-03-01
影响因子：
11.1
作者：
Feramisco, JD;Radhakrishnan, A;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
4.8
作者：
Cheng, D;Espenshade, PJ;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
3.8
作者：
Gao, Yuyan;Nan, Xianxiu;Liu, Shulin
通讯作者：
Liu, Shulin