PI(5)P Regulates Autophagosome Biogenesis

By M. Vicinanza, Viktor I. Korolchuk, Avraham Ashkenazi, C. Puri, Fiona M Menzies, J. Clarke, D. Rubinsztein. 2015

245 citations recorded by the source corpus.

Summary Phosphatidylinositol 3-phosphate (PI(3)P), the product of class III PI3K VPS34, recruits specific autophagic effectors, like WIPI2, during the initial steps of autophagosome biogenesis and thereby regulates canonical autophagy. However, mammalian cells can produce autophagosomes through enigmatic noncanonical VPS34-independent pathways. Here we show that PI(5)P can regulate autophagy via PI(3)P effectors and thereby identify a mechanistic explanation for forms of noncanonical autophagy. PI(5)P synthesis by the phosphatidylinositol 5-kinase PIKfyve was required for autophagosome biogenesis, and it increased levels of PI(5)P, stimulated autophagy, and reduced the levels of autophagic substrates. Inactivation of VPS34 impaired recruitment of WIPI2 and DFCP1 to autophagic precursors, reduced ATG5-ATG12 conjugation, and compromised autophagosome formation. However, these phenotypes were rescued by PI(5)P in VPS34-inactivated cells. These findings provide a mechanistic framework for alternative VPS34-independent autophagy-initiating pathways, like glucose starvation, and unravel a cytoplasmic function for PI(5)P, which previously has been linked predominantly to nuclear roles.

Subfields: Epidemiology, Physiology

How researchers see this paper

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

In Epidemiology

1. J. Clarke
2. Alec C. Kimmelman
3. N. Divecha

In Physiology

1. Lewis C. Cantley
2. J. Asara
3. Alec C. Kimmelman
4. D. Krainc

Citations in the corpus

• Molecular definitions of autophagy and related processes (2017, unknown): “Besides operating as a receptor for the recruitment of forming autophago-somes to invading bacteria, NDP52 supports autophagosome maturation upon interaction with LC3A, LC3B, LC3C, GABARAPL2, and myosin VI (MYO6) (von Muhlinen et al , 2012; Verlhac et al , 2015).”
• Targeting the PI5P4K lipid kinase family in cancer using covalent inhibitors (2020, background): “The criticai role of the PI5P4Ks in mediating autophagy may explain their induced essentiality in various disease pathologies (Emerling et al., 2013; Vicinanza et al., 2015; AlRamahi et al., 2017; Lundquist et al., 2018).”
• The lipid kinase PI5P4Kβ is an intracellular GTP sensor for metabolism and tumorigenesis (2016, unknown): “Binding of PI(5)P to WIPI2, an autophagy effector, has been shown to induce Vps34-independent non-canonical autophagy (Vicinanza et al., 2015).”
• Phosphatidylinositol-5-phosphate 4-kinases regulate cellular lipid metabolism by facilitating autophagy (2018, background): “The three PI5P4K isoforms have also been localized to autophagosomes, presumably to convert PI-5-P to PI-4,5-P2 at this location (Vicinanza et al., 2015).”
• Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein (2017, background): “The data presented in this manuscript demonstrates that pharmacological inhibition, or knockdown of PIP4Kg produce a similar reduction in huntingtin levels, and a concomitant elevation of PI5P and PI(3,5)P2 and PI3P.”