WIPI2 Links LC3 Conjugation with PI3P, Autophagosome Formation, and Pathogen Clearance by Recruiting Atg12–5-16L1
WIPI2 Links LC3 Conjugation with PI3P, Autophagosome Formation, and Pathogen Clearance by Recruiting Atg12–5-16L1
Mammalian cell homeostasis during starvation depends on initiation of autophagy by endoplasmic reticulum-localized phosphatidylinositol 3-phosphate (PtdIns(3)P) synthesis. Formation of double-membrane autophagosomes that engulf cytosolic components requires the LC3-conjugating Atg12-5-16L1 complex. The molecular mechanisms of Atg12-5-16L1 recruitment and significance of PtdIns(3)P synthesis at autophagosome formation sites are unknown. By identifying interacting partners of WIPIs, WD-repeat PtdIns(3)P effector proteins, we found that Atg16L1 directly binds WIPI2b. Mutation experiments and ectopic localization of WIPI2b to plasma membrane show that WIPI2b is a PtdIns(3)P effector upstream of Atg16L1 and is required for LC3 conjugation and starvation-induced autophagy through recruitment of the Atg12-5-16L1 complex. Atg16L1 mutants, which do not bind WIPI2b but bind FIP200, cannot rescue starvation-induced autophagy in Atg16L1-deficient MEFs. WIPI2b is also required for autophagic clearance of pathogenic bacteria. WIPI2b binds the membrane surrounding Salmonella and recruits the Atg12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella.
- Babraham Institute United Kingdom
- University of Toronto Canada
- Cancer Research UK United Kingdom
- London Research Institute United Kingdom
- University of Toronto / Department of Laboratory Medicine & Pathobiology
Molecular Sequence Data, Autophagy-Related Proteins, Article, Autophagy-Related Protein 5, Mice, Phagocytosis, Phosphatidylinositol Phosphates, Phagosomes, Autophagy, Animals, Humans, Amino Acid Sequence, Molecular Biology, Conserved Sequence, Membrane Proteins, Cell Biology, Intracellular Membranes, Phosphate-Binding Proteins, HEK293 Cells, Host-Pathogen Interactions, Carrier Proteins, Microtubule-Associated Proteins, Autophagy-Related Protein 12
Molecular Sequence Data, Autophagy-Related Proteins, Article, Autophagy-Related Protein 5, Mice, Phagocytosis, Phosphatidylinositol Phosphates, Phagosomes, Autophagy, Animals, Humans, Amino Acid Sequence, Molecular Biology, Conserved Sequence, Membrane Proteins, Cell Biology, Intracellular Membranes, Phosphate-Binding Proteins, HEK293 Cells, Host-Pathogen Interactions, Carrier Proteins, Microtubule-Associated Proteins, Autophagy-Related Protein 12
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