The TORC1-Regulated CPA Complex Rewires an RNA Processing Network to Drive Autophagy and Metabolic Reprogramming

Publication date: Available online 29 March 2018
Source:Cell Metabolism
Author(s): Hong-Wen Tang, Yanhui Hu, Chiao-Lin Chen, Baolong Xia, Jonathan Zirin, Min Yuan, John M. Asara, Leonard Rabinow, Norbert Perrimon
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.

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Teaser

Tang et al. investigate the mechanisms of how TORC1 regulates autophagy and cell metabolism. They demonstrate that CDK8 and DOA, two kinases downstream of TORC1 signaling, directly phosphorylate CPSF6 to regulate alternative mRNA polyadenylation and splicing and mediate TORC1-dependent physiological functions.


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