Portal de Periódicos da CAPES

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

2017; Cell Press; Volume: 171; Issue: 7 Linguagem: Inglês

10.1016/j.cell.2017.10.037

1097-4172

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

Lipid metabolism and biosynthesis

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.