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

Rui Liu, Lin-Wen Zeng, Rong Gong, Fanen Yuan, Hong-Bing Shu and Shu Li ()
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Rui Liu: Research Unit of Innate Immune and Inflammatory Diseases of the Chinese Academy of Medical Sciences
Lin-Wen Zeng: Research Unit of Innate Immune and Inflammatory Diseases of the Chinese Academy of Medical Sciences
Rong Gong: Wuhan University
Fanen Yuan: Wuhan University
Hong-Bing Shu: Research Unit of Innate Immune and Inflammatory Diseases of the Chinese Academy of Medical Sciences
Shu Li: Research Unit of Innate Immune and Inflammatory Diseases of the Chinese Academy of Medical Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24321-3

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