WIPI2 Links LC3 Conjugation with PI3P, Autophagosome Formation, and Pathogen Clearance by Recruiting Atg12–5-16L1

By H. C. Dooley, M. Razi, H. Polson, S. Girardin, Michael I. Wilson, S. Tooze. Molecules and Cells, 2014

832 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Epidemiology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/1fb132363a120e76fec2e9974370de2c2812b8b9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. N. Mizushima
2. Beth Levine
3. V. Deretic
4. Guido Kroemer
5. I. Slaninová
6. D. Klionsky
7. Douglas R. Green
8. Alec C. Kimmelman

In Epidemiology

1. Beth Levine
2. Guido Kroemer
3. N. Mizushima
4. I. Slaninová
5. D. Klionsky
6. V. Deretic
7. Douglas R. Green
8. L. Galluzzi

In Public Health, Environmental and Occupational Health

1. Beth Levine
2. Guido Kroemer
3. N. Mizushima
4. Douglas R. Green
5. V. Deretic
6. Alec C. Kimmelman
7. P. Codogno
8. L. Galluzzi

Citations in the corpus

• Molecular definitions of autophagy and related processes (2017, positive): “This enables the association of the PI3P-binding proteins DFCP1 and WIPI2 (Polson et al , 2010), the formation of ATG12-ATG5:ATG16L1 complexes, and consequent local LC3 lipidation (Dooley et al , 2014).”
• Autophagy pathway: Cellular and molecular mechanisms (2018, background): “This change in curvature may also facilitate exposure or clustering of PtdIns3P to allow recruitment of WIPI2B, which recruits the E3-like complex ATG12– ATG5-ATG16L1.”
• PI(5)P Regulates Autophagosome Biogenesis (2015, methodology): “Various myotubularin family members have been linked to autophagy, mainly in the regulation of PI3P metabolism (Taguchi-Atarashi et al., 2010; Vergne et al., 2009; Zou et al., 2012).”
• Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, neutral): “…it appears to aid the recruitment of WD repeat domain phosphoinositide-interacting (WIPI) proteins to the phagophore membrane, which, in turn, control the recruitment of crucial downstream autophagic proteins (e.g., ATG16L1 by WIPI2) that dictate where the phagophores form (Dooley et al., 2014).”