Pluto Bioinformatics

GSE132871: Reconstituted Rela-/- MEF

Bulk RNA sequencing

Protein deamidation is emerging as a post-translational modification that regulates protein function. The general role of protein deamidation is emerging asn fundamental to biological processes, yet remains is poorly understood. Here, we report that the rate-limiting enzyme of pyrimidine synthesis, a trifunctional enzyme containing activity of carbamoyl phosphate synthetase, aspartyl transcarbamoylase and dihydroorotase (CAD), deamidates the RelA subunit to inactivate NF-B and promote glycolysis. Functional screening and identified CAD as a negative regulator of NF-B activation, and biochemical analysis demonstrated that CAD deamidatesd RelA in vitro and in cellsto negate NF-B activation. D eamidated RelA, though failed to activate the expression of NF-B-dependent genes, thoughbut it up-regulated that of key glycolytic enzymes to promote glycolysis and cell proliferation. In proliferating cells, CAD is activated and catalyzes de novo pyrimidine synthesis to meet the metabolic need during S phase. CAD-mediated RelA deamidation and NF-B inactivation and glycolytic gene expression paralleled in a cell cycle-dependent mannerdriven by CAD-mediated RelA deamidation are necessary for cell proliferation. In addition, CAD promoted glycolysis via deamidated RelA that up-regulated the expression of key glycolytic enzymes. Stratification of cancer cell lines by CAD-mediated RelA deamidation predicted their sensitivity to inhibitors of glycolytic enzymes, while a subset of mutations predisposed RelA to deamidation and promoted glycolysis to enable cell proliferation. This work describes a process of metabolic reprogramming enabled by CAD-mediated RelA deamidation that underpins cell proliferation and tumorigenesis. SOURCE: Pinghui Feng (pinghuif@usc.edu) - Feng Lab Herman Ostrow School of Dentistry, University of Southern California