PI(5)P production by PIKFYVE is required for VPS34-independent autophagosome biogenesis.

  • Major finding: PI(5)P production by PIKFYVE is required for VPS34-independent autophagosome biogenesis.

  • Concept: PI(5)P rescues autophagy in PI(3)P-deficient cells and mediates glucose starvation–induced autophagy.

  • Impact: Components of this alternative autophagy pathway may represent potential therapeutic targets.

Autophagosomes are double-membraned vesicles that deliver damaged proteins and organelles and other cytoplasmic material to lysosomes during autophagy. The class III phosphatidylinositol 3-kinase VPS34 induces autophagosome formation by producing phosphatidylinositol 3-phosphate [PI(3)P], which in turn mediates membrane recruitment of proteins required for autophagosome biogenesis such as DFCP1 and WIPI2. However, noncanonical VPS34-independent autophagy has been observed, suggesting that other lipids and lipid kinases may regulate autophagy in certain contexts where PI(3)P is dispensable. Vicinanza and colleagues show that another phosphoinositide, phosphatidylinositol 5-phosphate [PI(5)P], which is synthesized by the type III PI(5)P kinase PIKFYVE, is present at early autophagic membranes and promotes autophagosome biogenesis in HeLa cells. Inhibition of PIKFYVE or overexpression of PI(5)P 4-kinases (PI5P4K2), which convert PI(5)P to phosphatidylinositol 4,5-bisphosphate, impaired autophagy, further pointing to a role of PI(5)P in autophagy initiation. In cells in which PI(3)P was depleted through inhibition or knockdown of VPS34, exogenous PI(5)P rescued autophagy and was also capable of recruiting DFCP1 and WIPI2. PI(5)P synthesis also was necessary for glucose starvation–induced autophagy in HeLa cells, whereas production of PI(3)P was not. The identification of PI(5)P as a regulator of autophagosome biogenesis provides insight into noncanonical autophagy mechanisms and may have potential therapeutic implications, as components of this pathway may contribute to resistance to inhibitors of VPS34-mediated autophagy currently in clinical development and possibly represent targets to inhibit autophagy-dependent prosurvival mechanisms employed by cancer cells in response to nutrient starvation.

Vicinanza M, Korolchuk VI, Ashkenazi A, Puri C, Menzies FM, Clarke JH, et al. PI(5)P regulates autophagosome biogenesis. Mol Cell 2015 Jan 8 [Epub ahead of print].

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