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.