Editors' ChoiceCell Biology

Intron splicing for lipid biosynthesis

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Sci. Signal.  23 Jan 2018:
Vol. 11, Issue 514, eaat0486
DOI: 10.1126/scisignal.aat0486

mTORC1 regulates de novo lipogenesis by enhancing the splicing of introns from transcripts encoding lipogenic enzymes.

The multiprotein complex mTORC1 (mechanistic target of rapamycin complex 1) couples environmental cues to cell growth and proliferation. Lee et al. found that mTORC1 regulated de novo lipogenesis, a biosynthetic process that generates the fatty acids and cholesterol required for plasma membrane expansion in proliferating cells. Activation of mTORC1 triggered the phosphorylation of SRPK2, a member of a family of kinases that phosphorylate the SR family of RNA-binding proteins, which are named for their serine/arginine (SR) repeat domains. Phosphorylation of SRPK2 involved multiple kinases and resulted in the relocalization of SRPK2 to the nucleus. Pharmacological mTORC1 inhibition or SRPK2 knockdown affected the expression and exon/intron usage of a common subset of genes, many of which encoded enzymes involved in de novo lipogenesis. However, promoter activity or activation of the transcription factor that targets these genes was not affected, suggesting a posttranscriptional mode of regulation. SRPK2-mediated phosphorylation of the SR protein SRSF1 promotes its interaction with U1-70k, a component of the spliceosome, and mTORC1 inhibition reduced the association of SRSF1 with U1-70k. Pre-mRNAs that encode lipogenic enzymes associated with SRSF1 and showed greater intron retention in mTORC1 inhibitor–treated or SRPK2-deficient cells, an effect that suggested inefficient intron splicing and which triggered nonsense-mediated decay. Genetic deficiency or pharmacological inhibition of SRPK2 suppressed the growth of xenografted cancer cells with high mTORC1 activity. Thus, regulation of de novo lipogenesis by mTORC1 through its effector SRPK2 is necessary for the growth of proliferating cells and may contribute to tumor growth.

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