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. |
---|---|
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.) |
References: | Nature. 2012 May 02;485(7396):109-13. (PMID: 22552098) Nat Chem Biol. 2018 May;14(5):466-473. (PMID: 29632410) Science. 2017 Jan 27;355(6323):. (PMID: 28126757) Neuron. 2011 Apr 14;70(1):66-81. (PMID: 21482357) Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):15790-7. (PMID: 26669439) Mol Cell. 2014 Nov 6;56(3):360-375. (PMID: 25284222) Mol Cell. 2011 Oct 21;44(2):304-16. (PMID: 22017876) Nat Commun. 2021 May 4;12(1):2522. (PMID: 33947846) Nat Methods. 2007 Mar;4(3):207-14. (PMID: 17327847) EMBO J. 2000 May 15;19(10):2161-7. (PMID: 10811607) Elife. 2016 Jun 09;5:. (PMID: 27278775) Nat Commun. 2020 Sep 18;11(1):4687. (PMID: 32948771) Cell. 2021 May 27;184(11):3022-3040.e28. (PMID: 33961781) Nature. 2017 Jul 6;547(7661):109-113. (PMID: 28658205) Mol Cell. 2021 Dec 16;81(24):5082-5098.e11. (PMID: 34699746) Mol Cell. 2020 Jan 2;77(1):150-163.e9. (PMID: 31708416) Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8977-82. (PMID: 22611195) Chembiochem. 2023 Aug 15;24(16):e202300108. (PMID: 37166757) J Cell Sci. 2022 Jul 15;135(14):. (PMID: 35833506) J Proteome Res. 2021 Jan 1;20(1):591-598. (PMID: 33190505) Elife. 2022 Dec 02;11:. (PMID: 36459484) Mol Cell Biol. 2014 Apr;34(7):1262-70. (PMID: 24449766) Mol Cell Proteomics. 2015 Sep;14(9):2394-404. (PMID: 25987413) Trends Biochem Sci. 2014 Nov;39(11):527-35. (PMID: 25220377) Mol Cell. 2005 Sep 16;19(6):829-40. (PMID: 16168377) Mol Biol Cell. 2003 Apr;14(4):1652-63. (PMID: 12686616) Science. 2006 Oct 20;314(5798):467-71. (PMID: 17053147) RSC Med Chem. 2024 Mar 5;15(3):1066-1071. (PMID: 38516600) Elife. 2018 Jun 18;7:. (PMID: 29911972) Autophagy. 2020 Sep;16(9):1618-1634. (PMID: 31795790) J Proteomics. 2016 Oct 4;148:85-93. (PMID: 27432472) Structure. 2015 Feb 3;23(2):364-73. (PMID: 25579817) Mol Cell. 2021 Jun 3;81(11):2445-2459.e13. (PMID: 33905682) Cell Rep. 2020 Aug 4;32(5):107944. (PMID: 32755570) Nature. 2012 Feb 22;485(7396):55-61. (PMID: 22367541) Cell. 2017 Dec 14;171(7):1545-1558.e18. (PMID: 29153836) Nat Commun. 2022 Jun 1;13(1):3041. (PMID: 35650207) J Biol Chem. 2023 Feb;299(2):102869. (PMID: 36621627) Mol Cell. 2012 Oct 26;48(2):242-53. (PMID: 22959274) EMBO Rep. 2021 Nov 4;22(11):e52981. (PMID: 34647674) Mol Biol Cell. 2008 Aug;19(8):3323-33. (PMID: 18508925) Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844) Sci Rep. 2019 Jul 8;9(1):9864. (PMID: 31285494) Nat Methods. 2011 Jul 10;8(8):691-6. (PMID: 21743460) Blood. 2020 Jan 16;135(3):208-219. (PMID: 31945154) Mol Cell. 2019 Jun 6;74(5):891-908.e10. (PMID: 31006537) Nature. 2021 Feb;590(7847):649-654. (PMID: 33627808) Cell. 2017 Mar 9;168(6):960-976. (PMID: 28283069) Mol Cell. 2021 Nov 18;81(22):4722-4735.e5. (PMID: 34626566) Endocrinology. 2003 Sep;144(9):3852-9. (PMID: 12933658) J Biol Chem. 2002 May 3;277(18):15309-16. (PMID: 11839765) Nature. 2020 Jul;583(7815):303-309. (PMID: 32612236) Nat Chem Biol. 2018 May;14(5):431-441. (PMID: 29581585) Mol Cell Proteomics. 2021;20:100016. (PMID: 33556866) Nat Commun. 2022 May 10;13(1):2542. (PMID: 35538051) Cell. 2010 Dec 23;143(7):1174-89. (PMID: 21183079) J Am Soc Mass Spectrom. 2015 Nov;26(11):1865-74. (PMID: 26115965) Nature. 2016 Aug 11;536(7615):184-9. (PMID: 27462806) Nature. 2020 Dec;588(7838):479-484. (PMID: 33177714) Cell Metab. 2013 Nov 5;18(5):698-711. (PMID: 24206664) Nat Cell Biol. 2019 Oct;21(10):1206-1218. (PMID: 31548609) Nat Biotechnol. 2006 Oct;24(10):1285-92. (PMID: 16964243) J Mol Biol. 2022 Jan 30;434(2):167347. (PMID: 34767800) J Mol Biol. 2010 May 14;398(4):497-506. (PMID: 20346956) Bioinformatics. 2010 Apr 1;26(7):966-8. (PMID: 20147306) Oncogene. 1996 Nov 7;13(9):1991-9. (PMID: 8934546) RNA. 2006 May;12(5):851-61. (PMID: 16540693) J Biol Chem. 2013 Jun 28;288(26):18707-15. (PMID: 23696639) Proteomics. 2013 Jan;13(1):22-4. (PMID: 23148064) Mol Cell. 2023 Sep 21;83(18):3333-3346.e5. (PMID: 37738964) PLoS One. 2013 Oct 15;8(10):e75217. (PMID: 24143168) Biochemistry. 2010 Jul 6;49(26):5588-99. (PMID: 20521764) Nat Methods. 2016 Sep;13(9):731-40. (PMID: 27348712) Science. 2022 Mar 11;375(6585):eabi6983. (PMID: 35271311) J Med Chem. 2023 Jan 12;66(1):149-169. (PMID: 36533617) Nature. 2016 Sep 14;537(7620):328-38. (PMID: 27629639) Mol Cell. 2024 Jan 18;84(2):293-308.e14. (PMID: 38113892) Cell. 2017 May 18;169(5):792-806. (PMID: 28525752) |
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 |
---|---|
DOI: | 10.1016/j.molcel.2024.04.026 |