mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway Journal Article
| Authors: | Yi, S. A.; Sepic, S.; Schulman, B. A.; Ordureau, A.; An, H. |
| Article Title: | mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway |
| 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. © 2024 |
| Keywords: | signal transduction; unclassified drug; genetics; ubiquitin; cell proliferation; proteome; metabolism; proteasome; proteasome endopeptidase complex; ubiquitin protein ligase; protein degradation; ubiquitination; mammalian target of rapamycin; adaptor proteins, signal transducing; multiprotein complexes; ubiquitin protein ligase e3; cell metabolism; signal transducing adaptor protein; ubiquitin-protein ligases; lysine; mtor; multiprotein complex; synthetase; hek293 cells; mammalian target of rapamycin complex 1; tor serine-threonine kinases; target of rapamycin kinase; proteolysis; ubiquitin-proteasome system; degrons; hydroxymethylglutaryl coenzyme a synthase; autophagic cell death; mevalonic acid; mtorc1; mevalonate pathway; humans; human; article; sterol; hydroxymethylglutaryl-coa synthase; degron; mechanistic target of rapamycin complex 1; ctlh; degradomics; hek293s cell line; gid; hmgcs1; 3 hydroxy 3 methylglutaryl coenzyme a; ctlh e3 ligase; hydroxymethylglutaryl coenzyme a synthase 1; lamtor5 protein, human; n degron; pro degron |
| Journal Title: | Molecular Cell |
| Volume: | 84 |
| Issue: | 11 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2024-06-06 |
| Start Page: | 2166 |
| End Page: | 2184.e9 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2024.04.026 |
| PUBMED: | 38788716 |
| PROVIDER: | scopus |
| PMCID: | PMC11186538 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Heeseon An -- Source: Scopus |
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