Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling

Cell. 2017 Dec 14;171(7):1545-1558.e18. doi: 10.1016/j.cell.2017.10.037. Epub 2017 Nov 16.

Abstract

mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling. Mechanistically, SRPK2 promotes SR protein binding to U1-70K to induce splicing of lipogenic pre-mRNAs. Inhibition of this signaling pathway leads to intron retention of lipogenic genes, which triggers nonsense-mediated mRNA decay. Genetic or pharmacological inhibition of SRPK2 blunts de novo lipid synthesis, thereby suppressing cell growth. These results thus reveal a novel role of mTORC1-SRPK2 signaling in post-transcriptional regulation of lipid metabolism and demonstrate that SRPK2 is a potential therapeutic target for mTORC1-driven metabolic disorders.

Keywords: CK1; RNA splicing; RNA stability; S6K1; SR proteins; SRPK2; cancer metabolism; de novo lipid synthesis; mTOR; nonsense-mediated decay.

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Cholesterol / metabolism
  • Fatty Acids / metabolism
  • Female
  • Gene Expression Regulation*
  • Heterografts
  • Humans
  • Lipogenesis*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Processing, Post-Transcriptional*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction*

Substances

  • Fatty Acids
  • Cholesterol
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • SRPK2 protein, human
  • ribosomal protein S6 kinase, 70kD, polypeptide 1