Deamidation Shunts RelA from Mediating Inflammation to Aerobic Glycolysis.

Abstract

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.

• Authors: Jun Zhao, Mao Tian, Shu Zhang, Alireza Delfarah, Ruoyun Gao, Youliang Rao, Ali Can Savas, Anjie Lu, Larissa Bubb, Xiao Lei, Rosa Moshirian, Wenjie Zhu, Cheng Peng, Taijiao Jiang, Lin Chen, Nicholas A Graham, Pinghui Feng
• Journal: Cell metabolism (Cell Metab) Vol. 31 Issue 5 Pg. 937-955.e7 (05 05 2020) ISSN: 1932-7420 [Electronic] United States
• PMID: 32325032 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• RELA protein, human
• Transcription Factor RelA

Topics

• Animals
• Cell Proliferation
• Cells, Cultured
• Glycolysis
• Humans
• Inflammation (metabolism)
• Male
• Mice
• Mice, Nude
• Mutation
• Transcription Factor RelA (genetics, metabolism)