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

Sci Signal. 2017 Jan 3;10(460):eaah4117. doi: 10.1126/scisignal.aah4117.


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

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Immunoblotting
  • Lipogenesis*
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphatidate Phosphatase / genetics
  • Phosphatidate Phosphatase / metabolism*
  • Phosphorylation
  • Protein Binding
  • Proteolysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Substrate Specificity
  • Ubiquitination


  • Nuclear Proteins
  • SKP Cullin F-Box Protein Ligases
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase