Post-translational Modifications of Beclin 1 Provide Multiple Strategies for Autophagy Regulation

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2018 Dec 15

PMID 30546075

Citations 102

Authors

Sandra M Hill

Lidia Wrobel

David C Rubinsztein

Affiliations

Soon will be listed here.

Abstract

Autophagy is a conserved intracellular degradation pathway essential for protein homeostasis, survival and development. Defects in autophagic pathways have been connected to a variety of human diseases, including cancer and neurodegeneration. In the process of macroautophagy, cytoplasmic cargo is enclosed in a double-membrane structure and fused to the lysosome to allow for digestion and recycling of material. Autophagosome formation is primed by the ULK complex, which enables the downstream production of PI(3)P, a key lipid signalling molecule, on the phagophore membrane. The PI(3)P is generated by the PI3 kinase (PI3K) complex, consisting of the core components VPS34, VPS15 and Beclin 1. Beclin 1 is a central player in autophagy and constitutes a molecular platform for the regulation of autophagosome formation and maturation. Post-translational modifications of Beclin 1 affect its stability, interactions and ability to regulate PI3K activity, providing the cell with a plethora of strategies to fine-tune the levels of autophagy. Being such an important regulator, Beclin 1 is a potential target for therapeutic intervention and interfering with the post-translational regulation of Beclin 1 could be one way of manipulating the levels of autophagy. In this review, we provide an overview of the known post-translational modifications of Beclin 1 that govern its role in autophagy and how these modifications are maintained by input from several upstream signalling pathways. ▓.

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References

Bento C, Renna M, Ghislat G, Puri C, Ashkenazi A, Vicinanza M . Mammalian Autophagy: How Does It Work?. Annu Rev Biochem. 2016; 85:685-713. DOI: 10.1146/annurev-biochem-060815-014556. View

Dikic I, Elazar Z . Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018; 19(6):349-364. DOI: 10.1038/s41580-018-0003-4. View

Farre J, Subramani S . Mechanistic insights into selective autophagy pathways: lessons from yeast. Nat Rev Mol Cell Biol. 2016; 17(9):537-52. PMC: 5549613. DOI: 10.1038/nrm.2016.74. View

Rubinsztein D, Bento C, Deretic V . Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J Exp Med. 2015; 212(7):979-90. PMC: 4493419. DOI: 10.1084/jem.20150956. View

Lamb C, Yoshimori T, Tooze S . The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol. 2013; 14(12):759-74. DOI: 10.1038/nrm3696. View

Liang X, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H . Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999; 402(6762):672-6. DOI: 10.1038/45257. View

Polson H, de Lartigue J, Rigden D, Reedijk M, Urbe S, Clague M . Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy. 2010; 6(4):506-22. DOI: 10.4161/auto.6.4.11863. View

Dooley H, Razi M, Polson H, Girardin S, Wilson M, Tooze S . WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell. 2014; 55(2):238-52. PMC: 4104028. DOI: 10.1016/j.molcel.2014.05.021. View

Gonzalez A, Hall M . Nutrient sensing and TOR signaling in yeast and mammals. EMBO J. 2017; 36(4):397-408. PMC: 5694944. DOI: 10.15252/embj.201696010. 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.

Bar-Peled L, Sabatini D . Regulation of mTORC1 by amino acids. Trends Cell Biol. 2014; 24(7):400-6. PMC: 4074565. DOI: 10.1016/j.tcb.2014.03.003. View

12.

Son S, Park S, Lee H, Siddiqi F, Lee J, Menzies F . Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A. Cell Metab. 2018; 29(1):192-201.e7. PMC: 6331339. DOI: 10.1016/j.cmet.2018.08.013. View

13.

Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y . Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009; 20(7):1981-91. PMC: 2663915. DOI: 10.1091/mbc.e08-12-1248. View

14.

Jung C, Jun C, Ro S, Kim Y, Otto N, Cao J . ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009; 20(7):1992-2003. PMC: 2663920. DOI: 10.1091/mbc.e08-12-1249. View

15.

Egan D, Chun M, Vamos M, Zou H, Rong J, Miller C . Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates. Mol Cell. 2015; 59(2):285-97. PMC: 4530630. DOI: 10.1016/j.molcel.2015.05.031. View

16.

Zhou C, Ma K, Gao R, Mu C, Chen L, Liu Q . Regulation of mATG9 trafficking by Src- and ULK1-mediated phosphorylation in basal and starvation-induced autophagy. Cell Res. 2016; 27(2):184-201. PMC: 5339848. DOI: 10.1038/cr.2016.146. View

17.

Park J, Jung C, Seo M, Otto N, Grunwald D, Kim K . The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy. 2016; 12(3):547-64. PMC: 4835982. DOI: 10.1080/15548627.2016.1140293. View

18.

Russell R, Tian Y, Yuan H, Park H, Chang Y, Kim J . ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol. 2013; 15(7):741-50. PMC: 3885611. DOI: 10.1038/ncb2757. View

19.

Garcia D, Shaw R . AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Mol Cell. 2017; 66(6):789-800. PMC: 5553560. DOI: 10.1016/j.molcel.2017.05.032. View

20.

Lee J, Park S, Takahashi Y, Wang H . The association of AMPK with ULK1 regulates autophagy. PLoS One. 2010; 5(11):e15394. PMC: 2972217. DOI: 10.1371/journal.pone.0015394. View