Molecular Cell
Volume 55, Issue 2, 17 July 2014, Pages 238-252
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Article
WIPI2 Links LC3 Conjugation with PI3P, Autophagosome Formation, and Pathogen Clearance by Recruiting Atg12–5-16L1

https://doi.org/10.1016/j.molcel.2014.05.021Get rights and content
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Highlights

  • WIPI2 binds Atg16L1 directly and recruits the Atg12–5-16L1 complex

  • WIPI2 binding to Atg16L1 is required for LC3 lipidation and autophagosome formation

  • WIPI2-Atg16L1 function requires PI3P binding by WIPI2 and is independent of FIP200

  • Autophagosomal engulfment of Salmonella requires the WIPI2-Atg16L1 complex

Summary

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.

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