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

Cell metabolism | 2018

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.

Pubmed ID: 29606597 RIS Download

Research resources used in this publication

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: P01 CA120964
  • Agency: NIAMS NIH HHS, United States
    Id: R01 AR057352
  • Agency: NCATS NIH HHS, United States
    Id: UL1 TR001102
  • Agency: Howard Hughes Medical Institute, United States

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This is a list of tools and resources that we have found mentioned in this publication.


Cytoscape (tool)

RRID:SCR_003032

Software platform for complex network analysis and visualization. Used for visualization of molecular interaction networks and biological pathways and integrating these networks with annotations, gene expression profiles and other state data.

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STAR (tool)

RRID:SCR_015899

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

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tximport (tool)

RRID:SCR_016752

Software R package for importing pseudoaligned reads into R for use with downstream differential expression analysis. Used for import and summarize transcript level estimates for transcript and gene level analysis.

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STAR (tool)

RRID:SCR_004463

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

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Autophagy-related 1 antibody (antibody)

RRID:AB_2568303

This polyclonal targets Atg1

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Anti-CLK2 (antibody)

RRID:AB_2722619

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HA-influenza (antibody)

RRID:AB_257974

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Mono- and polyubiquitinylated conjugates, mAb (FK2) (antibody)

RRID:AB_10541840

This monoclonal targets Mono- and polyubiquitinylated conjugates mAb (FK2)

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CPSF6 (L16) (antibody)

RRID:AB_1121901

This monoclonal targets Human CPSF6

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LC3B Antibody (antibody)

RRID:AB_915950

This polyclonal targets LC3B

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Cdk8 (D-9) (antibody)

RRID:AB_627244

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HA.11 Clone 16B12 Monoclonal Antibody, Purified (antibody)

RRID:AB_10064068

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Phospho-PKA Substrate (RRXS*/T*) (100G7E) Rabbit mAb (antibody)

RRID:AB_331817

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Phospho-Threonine/Tyrosine Antibody (antibody)

RRID:AB_330301

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p-Ser (16B4) (antibody)

RRID:AB_1128624

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Anti-GABARAPL1 / ATG8 Antibody (antibody)

RRID:AB_2722618

This polyclonal targets GABARAPL1 / ATG8

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ANTI-FLAG(R) M2 Affinity Gel (antibody)

RRID:AB_10063035

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GFP-Trap_A (antibody)

RRID:AB_2631357

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ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

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GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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w[1118]; Df(3L)BSC815, P+PBac{w[+mC]=XP3.WH3}BSC815/TM6C, Sb[1] cu[1] (organism)

RRID:BDSC_27576

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y[1] w[1] N[spl-1]; Df(3L)66C-G28/TM3, Sb[1] (organism)

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w[1118]; Df(3L)BSC376/TM6C, Sb[1] cu[1] (organism)

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w[1118]; Df(3L)BSC113/TM6B, Tb[1] (organism)

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w[*] P{w[+mC]=EP}G11096 (organism)

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RRID:BDSC_34639

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMS00923}attP2 (organism)

RRID:BDSC_33966

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMS01250}attP2 (organism)

RRID:BDSC_34936

Drosophila melanogaster with name y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMS01250}attP2 from BDSC.

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RRID:BDSC_9689

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y[1] v[1]; P{y[+t7.7] v[+t1.8]=TRiP.HMS00044}attP2 (organism)

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.GL01861}attP2 (organism)

RRID:BDSC_58355

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RRID:BDSC_31277

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y[1] v[1]; P{y[+t7.7] v[+t1.8]=TRiP.HMC02355}attP2/TM3, Sb[1] (organism)

RRID:BDSC_50893

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y[1] v[1]; P{y[+t7.7] v[+t1.8]=TRiP.GL01572}attP2 (organism)

RRID:BDSC_43227

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMC03910}attP40 (organism)

RRID:BDSC_55696

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMC03936}attP40 (organism)

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.GL01037}attP2 (organism)

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMC03912}attP40 (organism)

RRID:BDSC_55698

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.GL01166}attP2 (organism)

RRID:BDSC_42478

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RRID:BDSC_43273

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMS00671}attP2 (organism)

RRID:BDSC_32883

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RRID:BDSC_34804

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y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMS00406}attP2 (organism)

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y[1] v[1]; P{y[+t7.7] v[+t1.8]=TRiP.JF01355}attP2 (organism)

RRID:BDSC_31603

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RRID:CVCL_0031

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HEK293T/17 (cell line)

RRID:CVCL_1926

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Autophagy-related 1 antibody (antibody)

RRID:AB_2568303

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