Title | Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Lee, 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 |
Journal | Cell |
Volume | 171 |
Issue | 7 |
Pagination | 1545-1558.e18 |
Date Published | 2017 Dec 14 |
ISSN | 1097-4172 |
Keywords | Animals, 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> |
DOI | 10.1016/j.cell.2017.10.037 |
Alternate Journal | Cell |
PubMed ID | 29153836 |
PubMed Central ID | PMC5920692 |
Grant List | R01 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 |