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Deamidation Shunts RelA from Mediating Inflammation to Aerobic Glycolysis.
Cell Metabolism ( IF 27.7 ) Pub Date : 2020-04-22 , DOI: 10.1016/j.cmet.2020.04.006
Jun Zhao 1 , Mao Tian 1 , Shu Zhang 1 , Alireza Delfarah 2 , Ruoyun Gao 1 , Youliang Rao 1 , Ali Can Savas 1 , Anjie Lu 3 , Larissa Bubb 1 , Xiao Lei 4 , Rosa Moshirian 1 , Wenjie Zhu 5 , Cheng Peng 3 , Taijiao Jiang 6 , Lin Chen 4 , Nicholas A Graham 2 , Pinghui Feng 1
Affiliation  

Cell proliferation and inflammation are two metabolically demanding biological processes. How these competing processes are selectively executed in the same cell remains unknown. Here, we report that the enzyme carbamoyl-phosphate synthetase, aspartyl transcarbamoylase, and dihydroorotase (CAD) deamidates the RelA subunit of NF-κB in cancer cells to promote aerobic glycolysis and fuel cell proliferation in tumorigenesis. This post-translational modification switches RelA function from mediating the expression of NF-κB-responsive genes to that of glycolytic enzymes, thus shunting the cell's inflammatory response to aerobic glycolysis. Further, we profiled diverse human cancer cell lines and found that high CAD expression and a subset of RELA mutations correlated with RelA deamidation. And by use of inhibitors of key glycolytic enzymes, we validated the pivotal role of RelA deamidation in tumorigenesis of cancer cell lines. This work illuminates a mechanism by which protein deamidation selectively specifies gene expression and consequent biological processes.

中文翻译:

脱酰胺分流 RelA 从介导炎症到有氧糖酵解。

细胞增殖和炎症是两个需要代谢的生物过程。这些相互竞争的过程如何在同一个单元格中选择性地执行仍然未知。在这里,我们报告了氨甲酰磷酸合成酶、天冬氨酰转氨甲酰酶和二氢乳清酸酶 (CAD) 使癌细胞中 NF-κB 的 RelA 亚基脱酰胺,以促进肿瘤发生中的有氧糖酵解和燃料细胞增殖。这种翻译后修饰将 RelA 功能从介导 NF-κB 反应基因的表达转变为糖酵解酶的表达,从而使细胞对有氧糖酵解的炎症反应分流。此外,我们分析了不同的人类癌细胞系,发现高 CAD 表达和一部分 RELA 突变与 RelA 脱酰胺相关。并通过使用关键糖酵解酶抑制剂,我们验证了 RelA 脱酰胺在癌细胞系肿瘤发生中的关键作用。这项工作阐明了一种机制,通过该机制蛋白质脱酰胺选择性指定基因表达和随后的生物过程。
更新日期:2020-04-22
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