The SCFß-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis.
Sci Signal
; 10(460)2017 01 03.
Article
em En
| MEDLINE
| ID: mdl-28049764
ABSTRACT
The SCFß-TRCP E3 ubiquitin ligase complex plays pivotal roles in normal cellular physiology and in pathophysiological conditions. Identification of ß-transducin repeat-containing protein (ß-TRCP) substrates is therefore critical to understand SCFß-TRCP biology and function. We used a ß-TRCP-phosphodegron motif-specific antibody in a ß-TRCP substrate screen coupled with tandem mass spectrometry and identified multiple ß-TRCP substrates. One of these substrates was Lipin1, an enzyme and suppressor of the family of sterol regulatory element-binding protein (SREBP) transcription factors, which activate genes encoding lipogenic factors. We showed that SCFß-TRCP specifically interacted with and promoted the polyubiquitination of Lipin1 in a manner that required phosphorylation of Lipin1 by mechanistic target of rapamycin 1 (mTORC1) and casein kinase I (CKI). ß-TRCP depletion in HepG2 hepatocellular carcinoma cells resulted in increased Lipin1 protein abundance, suppression of SREBP-dependent gene expression, and attenuation of triglyceride synthesis. Moreover, ß-TRCP1 knockout mice showed increased Lipin1 protein abundance and were protected from hepatic steatosis induced by a high-fat diet. Together, these data reveal a critical physiological function of ß-TRCP in regulating hepatic lipid metabolic homeostasis in part through modulating Lipin1 stability.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfatidato Fosfatase
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Proteínas Nucleares
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Proteínas Ligases SKP Culina F-Box
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Lipogênese
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Fígado
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Sci Signal
Ano de publicação:
2017
Tipo de documento:
Article