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

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2018 Apr 3

PMID 29606597

Citations 34

Authors

Hong-Wen Tang

Yanhui Hu

Chiao-Lin Chen

Baolong Xia

Jonathan Zirin

Min Yuan

John M Asara

Leonard Rabinow

Norbert Perrimon

Affiliations

Soon will be listed here.

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.

Citing Articles

Transcriptional regulation of autophagy in skeletal muscle stem cells.

Gopal Krishnan P, Lee W, Goh K, Choy S, Turqueza L, Lim Z Dis Model Mech. 2025; 18(2).

PMID: 39925192 PMC: 11849978. DOI: 10.1242/dmm.052007.

FOXO-regulated DEAF1 controls muscle regeneration through autophagy.

Goh K, Lee W, Choy S, Priyadarshini G, Chua K, Tan Q Autophagy. 2024; 20(12):2632-2654.

PMID: 38963021 PMC: 11587838. DOI: 10.1080/15548627.2024.2374693.

mTORC1 is required for differentiation of germline stem cells in the Drosophila melanogaster testis.

Clemot M, DAlterio C, Kwang A, Jones D PLoS One. 2024; 19(3):e0300337.

PMID: 38512882 PMC: 10956854. DOI: 10.1371/journal.pone.0300337.

A distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study.

Chen H, Wang Z, Gong L, Wang Q, Chen W, Wang J Nat Commun. 2024; 15(1):1729.

PMID: 38409266 PMC: 10897204. DOI: 10.1038/s41467-024-46064-7.

Whole transcriptome screening for novel genes involved in meiosis and fertility in Drosophila melanogaster.

Sun S, Defosse T, Boyd A, Sop J, Verderose F, Surray D Sci Rep. 2024; 14(1):3602.

PMID: 38351116 PMC: 10864285. DOI: 10.1038/s41598-024-53346-z.

References

Mihaylova M, Shaw R . The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011; 13(9):1016-23. PMC: 3249400. DOI: 10.1038/ncb2329. View

Shi Y, Di Giammartino D, Taylor D, Sarkeshik A, Rice W, Yates 3rd J . Molecular architecture of the human pre-mRNA 3' processing complex. Mol Cell. 2009; 33(3):365-76. PMC: 2946185. DOI: 10.1016/j.molcel.2008.12.028. View

Rolland T, Tasan M, Charloteaux B, Pevzner S, Zhong Q, Sahni N . A proteome-scale map of the human interactome network. Cell. 2014; 159(5):1212-1226. PMC: 4266588. DOI: 10.1016/j.cell.2014.10.050. View

Guruharsha K, Rual J, Zhai B, Mintseris J, Vaidya P, Vaidya N . A protein complex network of Drosophila melanogaster. Cell. 2011; 147(3):690-703. PMC: 3319048. DOI: 10.1016/j.cell.2011.08.047. View

Kyburz A, Friedlein A, Langen H, Keller W . Direct interactions between subunits of CPSF and the U2 snRNP contribute to the coupling of pre-mRNA 3' end processing and splicing. Mol Cell. 2006; 23(2):195-205. DOI: 10.1016/j.molcel.2006.05.037. View

Housden B, Valvezan A, Kelley C, Sopko R, Hu Y, Roesel C . Identification of potential drug targets for tuberous sclerosis complex by synthetic screens combining CRISPR-based knockouts with RNAi. Sci Signal. 2015; 8(393):rs9. PMC: 4642709. DOI: 10.1126/scisignal.aab3729. View

Millevoi S, Loulergue C, Dettwiler S, Karaa S, Keller W, Antoniou M . An interaction between U2AF 65 and CF I(m) links the splicing and 3' end processing machineries. EMBO J. 2006; 25(20):4854-64. PMC: 1618107. DOI: 10.1038/sj.emboj.7601331. View

Zhao X, Feng D, Wang Q, Abdulla A, Xie X, Zhou J . Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1. J Clin Invest. 2012; 122(7):2417-27. PMC: 3386818. DOI: 10.1172/JCI61462. View

Miura P, Sanfilippo P, Shenker S, Lai E . Alternative polyadenylation in the nervous system: to what lengths will 3' UTR extensions take us?. Bioessays. 2014; 36(8):766-77. PMC: 4503322. DOI: 10.1002/bies.201300174. View

10.

Saxton R, Sabatini D . mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017; 169(2):361-371. DOI: 10.1016/j.cell.2017.03.035. View

11.

Feng D, Youn D, Zhao X, Gao Y, Quinn 3rd W, Xiaoli A . mTORC1 Down-Regulates Cyclin-Dependent Kinase 8 (CDK8) and Cyclin C (CycC). PLoS One. 2015; 10(6):e0126240. PMC: 4456374. DOI: 10.1371/journal.pone.0126240. View

12.

Hu G, McQuiston T, Bernard A, Park Y, Qiu J, Vural A . A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy. Nat Cell Biol. 2015; 17(7):930-942. PMC: 4528364. DOI: 10.1038/ncb3189. View

13.

Baier R, Picao-Osorio J, Alonso C . Molecular Regulation of Alternative Polyadenylation (APA) within the Drosophila Nervous System. J Mol Biol. 2017; 429(21):3290-3300. PMC: 5656104. DOI: 10.1016/j.jmb.2017.03.028. View

14.

Svoboda P, Di Cara A . Hairpin RNA: a secondary structure of primary importance. Cell Mol Life Sci. 2006; 63(7-8):901-8. PMC: 11136179. DOI: 10.1007/s00018-005-5558-5. View

15.

Tang H, Liao H, Peng W, Lin H, Chen C, Chen G . Atg9 interacts with dTRAF2/TRAF6 to regulate oxidative stress-induced JNK activation and autophagy induction. Dev Cell. 2013; 27(5):489-503. DOI: 10.1016/j.devcel.2013.10.017. View

16.

Cardinale S, Cisterna B, Bonetti P, Aringhieri C, Biggiogera M, Barabino S . Subnuclear localization and dynamics of the Pre-mRNA 3' end processing factor mammalian cleavage factor I 68-kDa subunit. Mol Biol Cell. 2007; 18(4):1282-92. PMC: 1838998. DOI: 10.1091/mbc.e06-09-0846. View

17.

Lee G, Zheng Y, Cho S, Jang C, England C, Dempsey J . Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling. Cell. 2017; 171(7):1545-1558.e18. PMC: 5920692. DOI: 10.1016/j.cell.2017.10.037. View

18.

Chang T, Shravage B, Hayes S, Powers C, Simin R, Harper J . Uba1 functions in Atg7- and Atg3-independent autophagy. Nat Cell Biol. 2013; 15(9):1067-78. PMC: 3762904. DOI: 10.1038/ncb2804. View

19.

Gabut M, Dejardin J, Tazi J, Soret J . The SR family proteins B52 and dASF/SF2 modulate development of the Drosophila visual system by regulating specific RNA targets. Mol Cell Biol. 2007; 27(8):3087-97. PMC: 1899935. DOI: 10.1128/MCB.01876-06. View

20.

Potter C, Huang H, Xu T . Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell. 2001; 105(3):357-68. DOI: 10.1016/s0092-8674(01)00333-6. View