The SCF?-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis.

ABSTRACT: The SCF?-TRCP E3 ubiquitin ligase complex plays pivotal roles in normal cellular physiology and in pathophysiological conditions. Identification of ?-transducin repeat-containing protein (?-TRCP) substrates is therefore critical to understand SCF?-TRCP biology and function. We used a ?-TRCP-phosphodegron motif-specific antibody in a ?-TRCP substrate screen coupled with tandem mass spectrometry and identified multiple ?-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 SCF?-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). ?-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, ?-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 ?-TRCP in regulating hepatic lipid metabolic homeostasis in part through modulating Lipin1 stability.

SUBMITTER: Shimizu K 

PROVIDER: S-EPMC5215841 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature