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

TitlePost-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling.
Publication TypeJournal Article
Year of Publication2017
AuthorsLee, G, Zheng, Y, Cho, S, Jang, C, England, C, Dempsey, JM, Yu, Y, Liu, X, He, L, Cavaliere, PM, Chavez, A, Zhang, E, Isik, M, Couvillon, A, Dephoure, NE, T Blackwell, K, Yu, JJ, Rabinowitz, JD, Cantley, LC, Blenis, J
JournalCell
Volume171
Issue7
Pagination1545-1558.e18
Date Published2017 Dec 14
ISSN1097-4172
KeywordsAnimals, Cell Nucleus, Cholesterol, Fatty Acids, Female, Gene Expression Regulation, Heterografts, Humans, Lipogenesis, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Nude, Neoplasm Transplantation, Protein-Serine-Threonine Kinases, Ribosomal Protein S6 Kinases, 70-kDa, RNA Processing, Post-Transcriptional, Signal Transduction
Abstract

<p>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.</p>

DOI10.1016/j.cell.2017.10.037
Alternate JournalCell
PubMed ID29153836
PubMed Central IDPMC5920692
Grant ListR01 HL121266 / HL / NHLBI NIH HHS / United States
R01 CA046595 / CA / NCI NIH HHS / United States
R01 HL138481 / HL / NHLBI NIH HHS / United States
R01 AG054215 / AG / NIA NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
R01 DK098331 / DK / NIDDK NIH HHS / United States
R01 GM114160 / GM / NIGMS NIH HHS / United States
P30 DK036836 / DK / NIDDK NIH HHS / United States
R01 GM051405 / GM / NIGMS NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
R35 CA197588 / CA / NCI NIH HHS / United States
R01 GM062891 / GM / NIGMS NIH HHS / United States
R35 GM122610 / GM / NIGMS NIH HHS / United States
R01 HL098216 / HL / NHLBI NIH HHS / United States
P30 CA016359 / CA / NCI NIH HHS / United States