Cell Metabolism
Volume 27, Issue 5, 1 May 2018, Pages 1040-1054.e8
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Article
The TORC1-Regulated CPA Complex Rewires an RNA Processing Network to Drive Autophagy and Metabolic Reprogramming

https://doi.org/10.1016/j.cmet.2018.02.023Get rights and content
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Highlights

  • TORC1 negatively inhibits CDK8 and DOA kinases

  • CDK8 and DOA phosphorylate CPSF6 to induce alternative RNA processing

  • Depletion of CPSF6 impairs autophagy and metabolic changes during starvation

  • The CDK8-CLK2/DOA-CPSF6 axis is conserved in mammals

Summary

Nutrient deprivation induces autophagy through inhibiting TORC1 activity. We describe a novel mechanism in Drosophila by which TORC1 regulates RNA processing of Atg transcripts and alters ATG protein levels and activities via the cleavage and polyadenylation (CPA) complex. We show that TORC1 signaling inhibits CDK8 and DOA kinases, which directly phosphorylate CPSF6, a component of the CPA complex. These phosphorylation events regulate CPSF6 localization, RNA binding, and starvation-induced alternative RNA processing of transcripts involved in autophagy, nutrient, and energy metabolism, thereby controlling autophagosome formation and metabolism. Similarly, we find that mammalian CDK8 and CLK2, a DOA ortholog, phosphorylate CPSF6 to regulate autophagy and metabolic changes upon starvation, revealing an evolutionarily conserved mechanism linking TORC1 signaling with RNA processing, autophagy, and metabolism.

Keywords

TORC1
CPA complex
CPSF6
RNA processing
autophagy
metabolism

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