ArticleMolecular cell2024
mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway.
Article in Molecular cell, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Glutamine-driven metabolic reprogramming promotes CAR-T cell function through mTOR-SREBP2 mediated HMGCS1 upregulation in ovarian cancer.Journal of translational medicine · 2025Trial
- The molecular glue CLEO4-88 inhibits the ACAA1 thiolase by induced binding to GID4.Nature chemical biology · 2026Article
- Molecular insights into NLRP1 Gly/N-degron recognition by CRL2Acta crystallographica. Section F, Structural biology communications · 2026Article
- Ubiquitylation by the GID/CTLH complex regulates the metabolic and innate immune response of macrophages to infection by Mycobacterium tuberculosis.PLoS pathogens · 2026Article
- Unconventional role of hydroxymethylglutaryl-CoA synthase 1 in driving pathogenic TScience advances · 2026Article
- Comprehensive Chemoproteomics Unveils Selective HMG-CoA Synthase 1 Inhibitors for Targeting Mevalonate Metabolism in Cancer.Journal of the American Chemical Society · 2026Article
- Proteomic Profiling Reveals How Physiological Media Reshape Cancer Cell Proteomes and Signaling Networks.Molecular & cellular proteomics : MCP · 2026Article
- Promoter Hypermethylation-Induced Silencing of FXYD1 Drives Breast Cancer Metastasis via DDX5-Mediated Wnt/β-Catenin Pathway Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- Proteome-wide C-degron activity profiling connects conditional regulation of the CTLH E3 ligase complex to ribosome biogenesis.bioRxiv : the preprint server for biology · 2026Article
- Loss of RanBP9 cooperates with p53 deficiency to promote sarcomagenesis.Frontiers in oncology · 2026Article
- The CTLH ubiquitin ligase substrates ZMYND19 and MKLN1 negatively regulate mTORC1 at the lysosomal membrane.Nature communications · 2025Article
- Article
- Degrons: defining the rules of protein degradation.Nature reviews. Molecular cell biology · 2025Review
- The many faces of the GID/CTLH E3 ligase complex.Biochemical Society transactions · 2025Review
- MKLN1-dependent GID4/CTLH E3 ubiquitin ligase complex assemblies are required to support B-cell antibody diversification.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- The generation and consequences of N-terminal proteoform diversity.Cell reports · 2025Review
- Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation.Nature structural & molecular biology · 2025Article
- RANBP9 and RANBP10 cooperate in regulating non-small cell lung cancer proliferation.Journal of experimental & clinical cancer research : CR · 2025Article
- Linker-free PROTACs efficiently induce the degradation of oncoproteins.Nature communications · 2025Article
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Authors and funding
5 authors.
Funding
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.
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Registered trials
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