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Systematic analysis of ATG13 domain requirements for autophagy induction

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posted on 2018-03-21, 12:21 authored by Nora Wallot-Hieke, Neha Verma, David Schlütermann, Niklas Berleth, Jana Deitersen, Philip Böhler, Fabian Stuhldreier, Wenxian Wu, Sabine Seggewiß, Christoph Peter, Holger Gohlke, Noboru Mizushima, Björn Stork

Macroautophagy/autophagy is an evolutionarily conserved cellular process whose induction is regulated by the ULK1 protein kinase complex. The subunit ATG13 functions as an adaptor protein by recruiting ULK1, RB1CC1 and ATG101 to a core ULK1 complex. Furthermore, ATG13 directly binds both phospholipids and members of the Atg8 family. The central involvement of ATG13 in complex formation makes it an attractive target for autophagy regulation. Here, we analyzed known interactions of ATG13 with proteins and lipids for their potential modulation of ULK1 complex formation and autophagy induction. Targeting the ATG101-ATG13 interaction showed the strongest autophagy-inhibitory effect, whereas the inhibition of binding to ULK1 or RB1CC1 had only minor effects, emphasizing that mutations interfering with ULK1 complex assembly do not necessarily result in a blockade of autophagy. Furthermore, inhibition of ATG13 binding to phospholipids or Atg8 proteins had only mild effects on autophagy. Generally, the observed phenotypes were more severe when autophagy was induced by MTORC1/2 inhibition compared to amino acid starvation. Collectively, these data establish the interaction between ATG13 and ATG101 as a promising target in disease-settings where the inhibition of autophagy is desired.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (STO 864/3-1; to B.S.); Deutsche Forschungsgemeinschaft (DFG) (STO 864/4-1; to B.S.); Deutsche Forschungsgemeinschaft (DFG) (STO 864/5-1; to B.S.); Deutsche Forschungsgemeinschaft (DFG) (GRK 2158/1; to H.G. and to B.S.) and Research Committee of the Medical Faculty of the Heinrich Heine University (22/2015; to B.S.).

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