Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes.

Covalent modification of LC3 and GABARAP proteins to phosphatidylethanolamine in the double-membrane phagophore is a key event in the early phase of macroautophagy, but can also occur on single-membrane structures. In both cases this involves transfer of LC3/GABARAP from ATG3 to phosphatidylethanolamine at the target membrane. Here we have purified ...
the full-length human ATG12-5-ATG16L1 complex and show its essential role in LC3B/GABARAP lipidation in vitro. We have identified two functionally distinct membrane-binding regions in ATG16L1. An N-terminal membrane-binding amphipathic helix is required for LC3B lipidation under all conditions tested. By contrast, the C-terminal membrane-binding region is dispensable for canonical autophagy but essential for VPS34-independent LC3B lipidation at perturbed endosomes. We further show that the ATG16L1 C-terminus can compensate for WIPI2 depletion to sustain lipidation during starvation. This C-terminal membrane-binding region is present only in the ?-isoform of ATG16L1, showing that ATG16L1 isoforms mechanistically distinguish between different LC3B lipidation mechanisms under different cellular conditions.
Mesh Terms:
Amino Acid Sequence, Animals, Autophagy, Autophagy-Related Proteins, Binding Sites, Cell Membrane, Endosomes, HEK293 Cells, Humans, Membrane Lipids, Mice, Microtubule-Associated Proteins, Protein Binding, Protein Isoforms, RAW 264.7 Cells, Sequence Homology, Amino Acid
Nat. Cell Biol.
Date: Dec. 01, 2018
Download Curated Data For This Publication
219369
Switch View:
  • Interactions 3