Structure and Function of the ULK1 Complex in Autophagy

Overview

Journal Curr Opin Cell Biol

Publisher Elsevier

Specialty Cell Biology

Date 2016 Feb 28

PMID 26921696

Citations 130

Authors

Mary G Lin

James H Hurley

Affiliations

Soon will be listed here.

Abstract

The ULK1 complex initiates autophagosome formation, linking cellular nutrient status to downstream events in autophagy. Recent work suggests that the ULK1 complex might also be activated in selective autophagy independent of nutrient or energy status. In this review we will discuss our current understanding of how the ULK1 complex is regulated by different signals, as well as how this complex then regulates other components of the autophagy machinery. Recently obtained structural data both on ULK1 and the orthologous yeast Atg1 complex are beginning to shed light on the higher-order organization of ULK1 complex. Ultimately, these insights might make it possible to understand how cargo organization and structure recruits and regulates ULK1 in selective autophagy initiation.

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References

Alemu E, Lamark T, Torgersen K, Birgisdottir A, Larsen K, Jain A . ATG8 family proteins act as scaffolds for assembly of the ULK complex: sequence requirements for LC3-interacting region (LIR) motifs. J Biol Chem. 2012; 287(47):39275-90. PMC: 3501051. DOI: 10.1074/jbc.M112.378109. View

Ragusa M, Stanley R, Hurley J . Architecture of the Atg17 complex as a scaffold for autophagosome biogenesis. Cell. 2012; 151(7):1501-1512. PMC: 3806636. DOI: 10.1016/j.cell.2012.11.028. View

Wu W, Tian W, Hu Z, Chen G, Huang L, Li W . ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep. 2014; 15(5):566-75. PMC: 4210082. DOI: 10.1002/embr.201438501. View

Stolz A, Ernst A, Dikic I . Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014; 16(6):495-501. DOI: 10.1038/ncb2979. View

Fujioka Y, Suzuki S, Yamamoto H, Kondo-Kakuta C, Kimura Y, Hirano H . Structural basis of starvation-induced assembly of the autophagy initiation complex. Nat Struct Mol Biol. 2014; 21(6):513-21. DOI: 10.1038/nsmb.2822. View

Baskaran S, Carlson L, Stjepanovic G, Young L, Kim D, Grob P . Architecture and dynamics of the autophagic phosphatidylinositol 3-kinase complex. Elife. 2014; 3. PMC: 4281882. DOI: 10.7554/eLife.05115. View

Lazarus M, Novotny C, Shokat K . Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors. ACS Chem Biol. 2015; 10(1):257-61. PMC: 4301081. DOI: 10.1021/cb500835z. View

Rui Y, Xu Z, Patel B, Chen Z, Chen D, Tito A . Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol. 2015; 17(3):262-75. PMC: 4344873. DOI: 10.1038/ncb3101. View

Lim J, Lachenmayer M, Wu S, Liu W, Kundu M, Wang R . Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet. 2015; 11(2):e1004987. PMC: 4344198. DOI: 10.1371/journal.pgen.1004987. View

10.

Suzuki S, Yamamoto H, Oikawa Y, Kondo-Kakuta C, Kimura Y, Hirano H . Atg13 HORMA domain recruits Atg9 vesicles during autophagosome formation. Proc Natl Acad Sci U S A. 2015; 112(11):3350-5. PMC: 4371973. DOI: 10.1073/pnas.1421092112. View

11.

Galluzzi L, Pietrocola F, Bravo-San Pedro J, Amaravadi R, Baehrecke E, Cecconi F . Autophagy in malignant transformation and cancer progression. EMBO J. 2015; 34(7):856-80. PMC: 4388596. DOI: 10.15252/embj.201490784. View

12.

Petherick K, Conway O, Mpamhanga C, Osborne S, Kamal A, Saxty B . Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. J Biol Chem. 2015; 290(18):11376-83. PMC: 4416842. DOI: 10.1074/jbc.C114.627778. View

13.

Ciuffa R, Lamark T, Tarafder A, Guesdon A, Rybina S, Hagen W . The selective autophagy receptor p62 forms a flexible filamentous helical scaffold. Cell Rep. 2015; 11(5):748-58. DOI: 10.1016/j.celrep.2015.03.062. View

14.

Kofinger J, Ragusa M, Lee I, Hummer G, Hurley J . Solution structure of the Atg1 complex: implications for the architecture of the phagophore assembly site. Structure. 2015; 23(5):809-818. PMC: 4426065. DOI: 10.1016/j.str.2015.02.012. View

15.

Suzuki H, Kaizuka T, Mizushima N, Noda N . Structure of the Atg101-Atg13 complex reveals essential roles of Atg101 in autophagy initiation. Nat Struct Mol Biol. 2015; 22(7):572-80. DOI: 10.1038/nsmb.3036. View

16.

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

17.

Kamber R, Shoemaker C, Denic V . Receptor-Bound Targets of Selective Autophagy Use a Scaffold Protein to Activate the Atg1 Kinase. Mol Cell. 2015; 59(3):372-81. PMC: 5602610. DOI: 10.1016/j.molcel.2015.06.009. View

18.

Lazarou M, Sliter D, Kane L, Sarraf S, Wang C, Burman J . The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015; 524(7565):309-314. PMC: 5018156. DOI: 10.1038/nature14893. View

19.

Lazarus M, Shokat K . Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1. Bioorg Med Chem. 2015; 23(17):5483-8. PMC: 4864979. DOI: 10.1016/j.bmc.2015.07.034. View

20.

Hieke N, Loffler A, Kaizuka T, Berleth N, Bohler P, Driessen S . Expression of a ULK1/2 binding-deficient ATG13 variant can partially restore autophagic activity in ATG13-deficient cells. Autophagy. 2015; 11(9):1471-83. PMC: 4590663. DOI: 10.1080/15548627.2015.1068488. View