GABARAPs regulate PI4P-dependent autophagosome: Lysosome fusion

Hanzhi Wang, Hui Qiao Sun, Xiaohui Zhu, Li Zhang, Joseph Albanesi, Beth Levine, Helen Yin

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

The Atg8 autophagy proteins are essential for autophagosome biogenesis and maturation. The γ-aminobutyric acid receptor-associated protein (GABARAP) Atg8 family is much less understood than the LC3 Atg8 family, and the relationship between the GABARAPs' previously identified roles as modulators of transmembrane protein trafficking and autophagy is not known. Here we report that GABARAPs recruit palmitoylated PI4KIIα, a lipid kinase that generates phosphatidylinositol 4-phosphate (PI4P) and binds GABARAPs, from the perinuclear Golgi region to autophagosomes to generate PI4P in situ. Depletion of either GABARAP or PI4KIIα, or overexpression of a dominant-negative kinase-dead PI4KIIα mutant, decreases autophagy flux by blocking autophagsome:lysosome fusion, resulting in the accumulation of abnormally large autophagosomes. The autophagosome defects are rescued by overexpressing PI4KIIα or by restoring intracellular PI4P through "PI4P shuttling." Importantly, PI4KIIα's role in autophagy is distinct from that of PI4KIIIβ and is independent of subsequent phosphatidylinositol 4,5 biphosphate (PIP2) generation. Thus, GABARAPs recruit PI4KIIα to autophagosomes, and PI4P generation on autophagosomes is critically important for fusion with lysosomes. Our results establish that PI4KIIα and PI4P are essential effectors of the GABARAP interactome's fusion machinery.

Original languageEnglish (US)
Pages (from-to)7015-7020
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number22
DOIs
StatePublished - Jun 2 2015

Keywords

  • Autophagosome:lysosome fusion
  • Autophagy
  • GABARAP
  • PI4KIIα
  • PI4P

ASJC Scopus subject areas

  • General

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