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

Gina Lee, Yuxiang Zheng, Sungyun Cho, Cholsoon Jang, Christina England, Jamie M. Dempsey, Yonghao Yu, Xiaolei Liu, Long He, Paola M. Cavaliere, Andre Chavez, Erik Zhang, Meltem Isik, Anthony Couvillon, Noah E. Dephoure, T. Keith Blackwell, Jane J. Yu, Joshua D. Rabinowitz, Lewis C. Cantley, John Blenis

Research output: Contribution to journalArticle

33 Scopus citations

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. An mTOR-dependent pathway is a key post-transcriptional regulator of lipogenic enzymes that are involved in tumor growth.

Original languageEnglish (US)
Pages (from-to)1545-1558.e18
JournalCell
Volume171
Issue number7
DOIs
StatePublished - Dec 14 2017

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Keywords

  • cancer metabolism
  • CK1
  • de novo lipid synthesis
  • mTOR
  • nonsense-mediated decay
  • RNA splicing
  • RNA stability
  • S6K1
  • SR proteins
  • SRPK2

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lee, G., Zheng, Y., Cho, S., Jang, C., England, C., Dempsey, J. M., Yu, Y., Liu, X., He, L., Cavaliere, P. M., Chavez, A., Zhang, E., Isik, M., Couvillon, A., Dephoure, N. E., Blackwell, T. K., Yu, J. J., Rabinowitz, J. D., Cantley, L. C., & Blenis, J. (2017). Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling. Cell, 171(7), 1545-1558.e18. https://doi.org/10.1016/j.cell.2017.10.037