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Publication

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

Cell | 2017

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.

Pubmed ID: 29153836 RIS Download

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Associated grants

Agency: NHLBI NIH HHS, United States
Id: R01 HL121266
Agency: NCI NIH HHS, United States
Id: R01 CA046595
Agency: NHLBI NIH HHS, United States
Id: R01 HL138481
Agency: NIA NIH HHS, United States
Id: R01 AG054215
Agency: NCI NIH HHS, United States
Id: P01 CA120964
Agency: NIDDK NIH HHS, United States
Id: R01 DK098331
Agency: NIGMS NIH HHS, United States
Id: R01 GM114160
Agency: NIDDK NIH HHS, United States
Id: P30 DK036836
Agency: NIGMS NIH HHS, United States
Id: R01 GM051405
Agency: NIGMS NIH HHS, United States
Id: R01 GM041890
Agency: NCI NIH HHS, United States
Id: R01 CA163591
Agency: NCI NIH HHS, United States
Id: R35 CA197588
Agency: NIGMS NIH HHS, United States
Id: R01 GM062891
Agency: NIGMS NIH HHS, United States
Id: R35 GM122610
Agency: NHLBI NIH HHS, United States
Id: R01 HL098216
Agency: NCI NIH HHS, United States
Id: P30 CA016359

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