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

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

  • Nat Commun. 2021 Jul 9;12(1):4227. doi: 10.1038/s41467-021-24321-3.
Rui Liu 1,  Lin-Wen Zeng 1,  Rong Gong 2,  Fanen Yuan 3,  Hong-Bing Shu 1,  Shu Li 4
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Research Unit of Innate Immune and Inflammatory Diseases of the Chinese Academy of Medical Sciences, Wuhan, China.
  • 2 Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
  • 3 Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 4 Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Research Unit of Innate Immune and Inflammatory Diseases of the Chinese Academy of Medical Sciences, Wuhan, China. shuli@whu.edu.cn.
PMID: 34244482 DOI: 10.1038/s41467-021-24321-3
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.

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