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Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0001-5123-135X
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2019 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 21, no 3, p. 372-383Article in journal (Refereed) Published
Abstract [en]

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 beta-isoform of ATG16L1, showing that ATG16L1 isoforms mechanistically distinguish between different LC3B lipidation mechanisms under different cellular conditions.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 21, no 3, p. 372-383
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Biophysics
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URN: urn:nbn:se:umu:diva-157525DOI: 10.1038/s41556-019-0274-9ISI: 000460120500012PubMedID: 30778222OAI: oai:DiVA.org:umu-157525DiVA, id: diva2:1301974
Available from: 2019-04-03 Created: 2019-04-03 Last updated: 2019-04-03Bibliographically approved

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Carlsson, Sven R

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