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

Hong-Wen Tang; Yanhui Hu; Chiao-Lin Chen; Baolong Xia; Jonathan Zirin; Min Yuan; John M Asara; Leonard Rabinow; Norbert Perrimon

doi:10.1016/j.cmet.2018.02.023

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

Cell Metab. 2018 May 1;27(5):1040-1054.e8. doi: 10.1016/j.cmet.2018.02.023. Epub 2018 Mar 29.

Authors

Hong-Wen Tang¹, Yanhui Hu², Chiao-Lin Chen², Baolong Xia², Jonathan Zirin², Min Yuan³, John M Asara³, Leonard Rabinow², Norbert Perrimon⁴

Affiliations

¹ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: [email protected].
² Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
⁴ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: [email protected].

Abstract

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: CPA complex; CPSF6; RNA processing; TORC1; autophagy; metabolism.

MeSH terms

Animals
Autophagy / genetics*
Autophagy-Related Protein 8 Family / genetics*
Autophagy-Related Protein-1 Homolog / genetics*
Cyclin-Dependent Kinase 8 / genetics
Cyclin-Dependent Kinase 8 / metabolism
Drosophila Proteins / genetics*
Drosophila Proteins / metabolism
Drosophila Proteins / physiology*
Drosophila melanogaster / genetics
Drosophila melanogaster / metabolism*
Energy Metabolism / genetics
Gene Expression Regulation
HEK293 Cells
Humans
MCF-7 Cells
Phosphorylation
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / metabolism
RNA / genetics
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Signal Transduction
Transcription Factors / genetics
Transcription Factors / physiology*
Transcription, Genetic
mRNA Cleavage and Polyadenylation Factors / metabolism*

Substances

Autophagy-Related Protein 8 Family
Cpsf6 protein, Drosophila
Drosophila Proteins
RNA-Binding Proteins
TORC1 protein complex, Drosophila
Transcription Factors
mRNA Cleavage and Polyadenylation Factors
RNA
Clk dual-specificity kinases
Doa protein, Drosophila
Protein-Tyrosine Kinases
Atg1 protein, Drosophila
Autophagy-Related Protein-1 Homolog
Protein Serine-Threonine Kinases
CDK8 protein, human
Cdk8 protein, Drosophila
Cyclin-Dependent Kinase 8

Abstract

MeSH terms

Substances

Grants and funding