2. Academic Validation
  3. mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway

mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway

  • Mol Cell. 2024 May 20:S1097-2765(24)00393-9. doi: 10.1016/j.molcel.2024.04.026.
Sang Ah Yi 1,  Sara Sepic 2,  Brenda A Schulman 3,  Alban Ordureau 4,  Heeseon An 5
Affiliations

Affiliations

  • 1 Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany; Technical University of Munich, School of Natural Sciences, Munich, Germany.
  • 3 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany; Technical University of Munich, School of Natural Sciences, Munich, Germany; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4 Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Tri-Institutional PhD Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: anh@mskcc.org.
PMID: 38788716 DOI: 10.1016/j.molcel.2024.04.026
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.

Keywords

CTLH; GID; HMGCS1; degradomics; mTOR; mTORC1; mevalonate pathway; sterol; ubiquitin; ubiquitin-proteasome system.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134904
    mTORC1抑制剂
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z