mTORC1 activity regulates post-translational modifications of glycine decarboxylase to modulate glycine metabolism and tumorigenesis.

Glycine decarboxylase (GLDC) is a key enzyme of glycine cleavage system that converts glycine into one-carbon units. GLDC is commonly up-regulated and plays important roles in many human cancers. Whether and how GLDC is regulated by post-translational modifications is unknown. Here we report that mechanistic target of rapamycin complex 1 ...
(mTORC1) signal inhibits GLDC acetylation at lysine (K) 514 by inducing transcription of the deacetylase sirtuin 3 (SIRT3). Upon inhibition of mTORC1, the acetyltransferase acetyl-CoA acetyltransferase 1 (ACAT1) catalyzes GLDC K514 acetylation. This acetylation of GLDC impairs its enzymatic activity. In addition, this acetylation of GLDC primes for its K33-linked polyubiquitination at K544 by the ubiquitin ligase NF-X1, leading to its degradation by the proteasomal pathway. Finally, we find that GLDC K514 acetylation inhibits glycine catabolism, pyrimidines synthesis and glioma tumorigenesis. Our finding reveals critical roles of post-translational modifications of GLDC in regulation of its enzymatic activity, glycine metabolism and tumorigenesis, and provides potential targets for therapeutics of cancers such as glioma.
Mesh Terms:
Acetyl-CoA C-Acetyltransferase, Acetylation, Animals, Carcinogenesis, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Glioma, Glycine, Glycine Dehydrogenase (Decarboxylating), HEK293 Cells, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational, Proteolysis, Pyrimidines, Repressor Proteins, Sirtuin 3, Transcriptional Activation, Ubiquitination, Xenograft Model Antitumor Assays
Nat Commun
Date: Jul. 09, 2021
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