한빛사논문
- 조회441
Sang Ah Yi,1 Sara Sepic,2,3 Brenda A. Schulman,2,3,4 Alban Ordureau,5 and Heeseon An 1,6,7,*
1Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 2Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
3Technical University of Munich, School of Natural Sciences, Munich, Germany
4Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
5Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
6Tri-Institutional PhD Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
7Lead contact
*Corresponding author: correspondence to Heeseon An
Abstract
Mammalian target of rapamycin (mTOR) senses changes in nutrient status and stimulates the autophagic process to recycle amino acids. However, the impact of nutrient stress on protein degradation beyond autophagic turnover is incompletely understood. We report that several metabolic enzymes are proteasomal targets regulated by mTOR activity based on comparative proteome degradation analysis. In particular, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) synthase 1 (HMGCS1), the initial enzyme in the mevalonate pathway, exhibits the most significant half-life adaptation. Degradation of HMGCS1 is regulated by the C-terminal to LisH (CTLH) E3 ligase through the Pro/N-degron motif. HMGCS1 is ubiquitylated on two C-terminal lysines during mTORC1 inhibition, and efficient degradation of HMGCS1 in cells requires a muskelin adaptor. Importantly, modulating HMGCS1 abundance has a dose-dependent impact on cell proliferation, which is restored by adding a mevalonate intermediate. Overall, our unbiased degradomics study provides new insights into mTORC1 function in cellular metabolism: mTORC1 regulates the stability of limiting metabolic enzymes through the ubiquitin system.
논문정보
- Research article
- 2024년 05월 (BRIC 등록일 2024-05-24)
- 국외 연구진
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