2. Academic Validation
  3. Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine

Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine

  • Mol Cell. 2021 May 6;81(9):2031-2040.e8. doi: 10.1016/j.molcel.2021.03.020.
Joanne Durgan 1,  Alf H Lystad 2,  Katherine Sloan 1,  Sven R Carlsson 3,  Michael I Wilson 1,  Elena Marcassa 4,  Rachel Ulferts 4,  Judith Webster 5,  Andrea F Lopez-Clavijo 6,  Michael J Wakelam 7,  Rupert Beale 4,  Anne Simonsen 2,  David Oxley 5,  Oliver Florey 8
Affiliations

Affiliations

  • 1 Signalling Programme, Babraham Institute, Cambridge, UK.
  • 2 Department of Molecular Medicine, University of Oslo, Oslo, Norway.
  • 3 Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
  • 4 Francis Crick Institute, London, UK.
  • 5 Mass Spectrometry Facility, Babraham Institute, Cambridge, UK.
  • 6 Lipidomics Facility, Babraham Institute, Cambridge, UK.
  • 7 Signalling Programme, Babraham Institute, Cambridge, UK; Lipidomics Facility, Babraham Institute, Cambridge, UK.
  • 8 Signalling Programme, Babraham Institute, Cambridge, UK. Electronic address: oliver.florey@babraham.ac.uk.
PMID: 33909989 DOI: 10.1016/j.molcel.2021.03.020
Abstract

Autophagy is a fundamental catabolic process that uses a unique post-translational modification, the conjugation of ATG8 protein to phosphatidylethanolamine (PE). ATG8 lipidation also occurs during non-canonical Autophagy, a parallel pathway involving conjugation of ATG8 to single membranes (CASM) at endolysosomal compartments, with key functions in immunity, vision, and neurobiology. It is widely assumed that CASM involves the same conjugation of ATG8 to PE, but this has not been formally tested. Here, we discover that all ATG8s can also undergo alternative lipidation to phosphatidylserine (PS) during CASM, induced pharmacologically, by LC3-associated phagocytosis or influenza A virus Infection, in mammalian cells. Importantly, ATG8-PS and ATG8-PE adducts are differentially delipidated by the Atg4 family and bear different cellular dynamics, indicating significant molecular distinctions. These results provide important insights into Autophagy signaling, revealing an alternative form of the hallmark ATG8 lipidation event. Furthermore, ATG8-PS provides a specific "molecular signature" for the non-canonical Autophagy pathway.

Keywords

ATG4; ATG8; LC3-associated phagocytosis; non-canonical autophagy; phosphatidylserine.

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