Deamidation Shunts RelA from Mediating Inflammation to Aerobic Glycolysis

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 carbamoyl phosphate synthetase, aspartyl transcarbamoylase and dihydroorotase (CAD) deamidates the RelA subunit of NF-kappaB 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-kappaB-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.

细胞增殖与炎症是两类代谢需求旺盛的生物学过程。目前尚不明确这两种相互竞争的过程如何在同一细胞内被选择性执行。本研究发现，氨甲酰磷酸合成酶、天冬氨酸转氨甲酰酶及二氢乳清酸酶（carbamoyl phosphate synthetase, aspartyl transcarbamoylase and dihydroorotase, CAD）可在癌细胞中对核因子κB（NF-κB）的RelA亚基进行脱酰胺修饰，从而促进有氧糖酵解，为肿瘤发生过程中的细胞增殖供能。该翻译后修饰将RelA的功能从介导核因子κB应答基因的表达，转变为调控糖酵解酶基因的表达，由此将细胞的炎症应答转向有氧糖酵解通路。进一步研究中，我们对多种人类癌细胞系开展了表达谱分析，发现CAD高表达以及部分RELA基因突变与RelA脱酰胺修饰存在相关性。此外，通过使用关键糖酵解酶抑制剂，我们验证了RelA脱酰胺修饰在癌细胞系肿瘤发生过程中的关键作用。本研究阐明了蛋白质脱酰胺作用选择性调控基因表达、进而决定后续生物学进程的一种分子机制。