TY - JOUR
T1 - Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth
AU - Cheng, Chunming
AU - Geng, Feng
AU - Li, Zoe
AU - Zhong, Yaogang
AU - Wang, Huabao
AU - Cheng, Xiang
AU - Zhao, Yue
AU - Mo, Xiaokui
AU - Horbinski, Craig
AU - Duan, Wenrui
AU - Chakravarti, Arnab
AU - Cheng, Xiaolin
AU - Guo, Deliang
N1 - Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke and the National Cancer Institute (USA) grants NS104332, NS112935 and R01CA240726 to D.G., CA227874 to D.G. and A.C. and an American Cancer Society Research Scholar Grant RSG-14-228-01–CSM to D.G. We also appreciate the support from the OSU Comprehensive Cancer Center–Pelotonia Idea grant and Urban & Shelly Meyer Fund for Cancer Research to D.G. The authors thank M. Torres for editorial assistance.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/5
Y1 - 2022/5
N2 - 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.
AB - 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.
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U2 - 10.1038/s42255-022-00568-y
DO - 10.1038/s42255-022-00568-y
M3 - Article
C2 - 35534729
AN - SCOPUS:85129766767
VL - 4
SP - 575
EP - 588
JO - Nature Metabolism
JF - Nature Metabolism
SN - 2522-5812
IS - 5
ER -
