2. Academic Validation
  3. 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

  • Mol Cell. 2014 Jul 17;55(2):238-52. doi: 10.1016/j.molcel.2014.05.021.
Hannah C Dooley 1,  Minoo Razi 1,  Hannah E J Polson 1,  Stephen E Girardin 2,  Michael I Wilson 3,  Sharon A Tooze 4
Affiliations

Affiliations

  • 1 London Research Institute, Cancer Research UK, 44 Lincolns Inn Fields, London WC2A 3LY, UK.
  • 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 3 The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
  • 4 London Research Institute, Cancer Research UK, 44 Lincolns Inn Fields, London WC2A 3LY, UK. Electronic address: sharon.tooze@cancer.org.uk.
PMID: 24954904 DOI: 10.1016/j.molcel.2014.05.021
Abstract

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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