Regulation of LC3 lipidation by the autophagy-specific class III phosphatidylinositol-3 kinase complex.

Molecular Biology of the Cell
Livia W BrierRandy Schekman

Abstract

Autophagy is a conserved eukaryotic pathway critical for cellular adaptation to changes in nutrition levels and stress. The class III phosphatidylinositol (PI)3-kinase complexes I and II (PI3KC3-C1 and -C2) are essential for autophagosome initiation and maturation, respectively, from highly curved vesicles. We used a cell-free reaction that reproduces a key autophagy initiation step, LC3 lipidation, as a biochemical readout to probe the role of autophagy-related gene (ATG)14, a PI3KC3-C1-specific subunit implicated in targeting the complex to autophagy initiation sites. We reconstituted LC3 lipidation with recombinant PI3KC3-C1, -C2, or various mutant derivatives added to extracts derived from a CRISPR/Cas9-generated ATG14-knockout cell line. Both complexes C1 and C2 require the C-terminal helix of VPS34 for activity on highly curved membranes. However, only complex C1 supports LC3 lipidation through the curvature-targeting amphipathic lipid packing sensor (ALPS) motif of ATG14. Furthermore, the ALPS motif and VPS34 catalytic activity are required for downstream recruitment of WD-repeat domain phosphoinositide-interacting protein (WIPI)2, a protein that binds phosphatidylinositol 3-phosphate and its product phosphatidylinositol...Continue Reading

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Citations

May 22, 2020·The Journal of Cell Biology·Dorotea FracchiollaSascha Martens
Aug 20, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Simone CarottiUmberto Vespasiani-Gentilucci
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Mar 16, 2021·Frontiers in Oncology·Maria Paz Hernández-CáceresCristina Bertocchi
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Aug 23, 2021·Biochimica Et Biophysica Acta. Biomembranes·Marina N IriondoAlicia Alonso

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Methods Mentioned

BETA
lipidation
protein-assay

Software Mentioned

ImageJ

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