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

Yi, Sang Ah; Sepic, Sara; Schulman, Brenda A; Ordureau, Alban; An, Heeseon

Yi, Sang Ah; Sepic, Sara; Schulman, Brenda A; Ordureau, Alban; An, Heeseon.

Afiliación

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.

Mol Cell ; 84(11): 2166-2184.e9, 2024 Jun 06.

Article en En | MEDLINE | ID: mdl-38788716

ABSTRACT

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.

Asunto(s)

Proliferación Celular; Hidroximetilglutaril-CoA Sintasa; Diana Mecanicista del Complejo 1 de la Rapamicina; Proteolisis; Ubiquitina-Proteína Ligasas; Ubiquitinación; Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo; Diana Mecanicista del Complejo 1 de la Rapamicina/genética; Humanos; Ubiquitina-Proteína Ligasas/metabolismo; Ubiquitina-Proteína Ligasas/genética; Células HEK293; Hidroximetilglutaril-CoA Sintasa/metabolismo; Hidroximetilglutaril-CoA Sintasa/genética; Complejo de la Endopetidasa Proteasomal/metabolismo; Complejo de la Endopetidasa Proteasomal/genética; Serina-Treonina Quinasas TOR/metabolismo; Serina-Treonina Quinasas TOR/genética; Ácido Mevalónico/metabolismo; Complejos Multiproteicos/metabolismo; Complejos Multiproteicos/genética; Transducción de Señal; Degrones; Proteínas Adaptadoras Transductoras de Señales

Palabras clave

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

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ubiquitina-Proteína Ligasas / Proliferación Celular / Ubiquitinación / Proteolisis / Diana Mecanicista del Complejo 1 de la Rapamicina / Hidroximetilglutaril-CoA Sintasa Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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