2. Academic Validation
  3. TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease

TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease

  • EMBO Rep. 2020 Jan 7;21(1):e48317. doi: 10.15252/embr.201948317.
Lina Herhaus 1,  Ramachandra M Bhaskara 2,  Alf Håkon Lystad 3,  Uxía Gestal-Mato 1,  Adriana Covarrubias-Pinto 1,  Florian Bonn 1,  Anne Simonsen 3,  Gerhard Hummer 2 4,  Ivan Dikic 1 5
Affiliations

Affiliations

  • 1 Institute of Biochemistry II, School of Medicine, Goethe University, Frankfurt am Main, Germany.
  • 2 Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany.
  • 3 Department of Molecular Medicine, Faculty of Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • 4 Institute for Biophysics, Goethe University, Frankfurt am Main, Germany.
  • 5 Buchmann Institute for Molecular Life Sciences, Riedberg Campus, Goethe University Frankfurt, Frankfurt am Main, Germany.
PMID: 31709703 DOI: 10.15252/embr.201948317
Abstract

Autophagy is a highly conserved catabolic process through which defective or otherwise harmful cellular components are targeted for degradation via the lysosomal route. Regulatory pathways, involving post-translational modifications such as phosphorylation, play a critical role in controlling this tightly orchestrated process. Here, we demonstrate that TBK1 regulates Autophagy by phosphorylating Autophagy modifiers LC3C and GABARAP-L2 on surface-exposed serine residues (LC3C S93 and S96; GABARAP-L2 S87 and S88). This phosphorylation event impedes their binding to the processing Enzyme ATG4 by destabilizing the complex. Phosphorylated LC3C/GABARAP-L2 cannot be removed from liposomes by Atg4 and are thus protected from ATG4-mediated premature removal from nascent autophagosomes. This ensures a steady coat of lipidated LC3C/GABARAP-L2 throughout the early steps in autophagosome formation and aids in maintaining a unidirectional flow of the autophagosome to the lysosome. Taken together, we present a new regulatory mechanism of Autophagy, which influences the conjugation and de-conjugation of LC3C and GABARAP-L2 to autophagosomes by TBK1-mediated phosphorylation.

Keywords

ATG4; ATG8; TBK1; autophagy; phosphorylation.

Figures