دورية أكاديمية
mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway.
| العنوان: | mTORC1-CTLH E3 ligase regulates the degradation of HMG-CoA synthase 1 through the Pro/N-degron pathway. |
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| المؤلفون: | Yi SA; Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Sepic S; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany; Technical University of Munich, School of Natural Sciences, Munich, Germany., Schulman BA; 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., Ordureau A; Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., An H; 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. |
| المصدر: | Molecular cell [Mol Cell] 2024 Jun 06; Vol. 84 (11), pp. 2166-2184.e9. Date of Electronic Publication: 2024 May 23. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Cambridge Ma : Cell Press Original Publication: Cambridge, Mass. : Cell Press, c1997- |
| مواضيع طبية MeSH: | Mechanistic Target of Rapamycin Complex 1*/metabolism , Mechanistic Target of Rapamycin Complex 1*/genetics , Ubiquitin-Protein Ligases*/metabolism , Ubiquitin-Protein Ligases*/genetics , Proteolysis* , Hydroxymethylglutaryl-CoA Synthase*/metabolism , Hydroxymethylglutaryl-CoA Synthase*/genetics , Ubiquitination* , Cell Proliferation*, Humans ; HEK293 Cells ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Endopeptidase Complex/genetics ; TOR Serine-Threonine Kinases/metabolism ; TOR Serine-Threonine Kinases/genetics ; Mevalonic Acid/metabolism ; Multiprotein Complexes/metabolism ; Multiprotein Complexes/genetics ; Signal Transduction ; Degrons ; Adaptor Proteins, Signal Transducing |
| مستخلص: | 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. Competing Interests: Declaration of interests The authors declare no competing interests. (Published by Elsevier Inc.) |
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| معلومات مُعتمدة: | P30 CA008748 United States CA NCI NIH HHS; R01 GM152667 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: CTLH; GID; HMGCS1; degradomics; mTOR; mTORC1; mevalonate pathway; sterol; ubiquitin; ubiquitin-proteasome system |
| المشرفين على المادة: | EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) EC 2.3.2.27 (Ubiquitin-Protein Ligases) EC 2.3.3.10 (Hydroxymethylglutaryl-CoA Synthase) EC 3.4.25.1 (Proteasome Endopeptidase Complex) EC 2.7.11.1 (TOR Serine-Threonine Kinases) S5UOB36OCZ (Mevalonic Acid) 0 (Multiprotein Complexes) 0 (LAMTOR5 protein, human) 0 (Adaptor Proteins, Signal Transducing) |
| تواريخ الأحداث: | Date Created: 20240524 Date Completed: 20240607 Latest Revision: 20240620 |
| رمز التحديث: | 20240620 |
| مُعرف محوري في PubMed: | PMC11186538 |
| DOI: | 10.1016/j.molcel.2024.04.026 |
| PMID: | 38788716 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1097-4164 |
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| DOI: | 10.1016/j.molcel.2024.04.026 |