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PI(5)P regulates autophagosome biogenesis

Mariella Vicinanza1, Viktor I Korolchuk1, Avraham Ashkenazi1

  • 1Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.

Molecular Cell
|January 13, 2015
PubMed

Insights

Phosphatidylinositol 5-phosphate (PI(5)P) drives noncanonical autophagy by influencing PI(3)P effectors. This reveals a novel cytoplasmic role for PI(5)P and explains VPS34-independent autophagosome formation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Autophagy Research

Background:

  • Canonical autophagy relies on phosphatidylinositol 3-phosphate (PI(3)P), produced by VPS34, to recruit effectors like WIPI2 for autophagosome biogenesis.
  • Mammalian cells exhibit noncanonical autophagy pathways independent of VPS34, the mechanisms of which remain unclear.

Purpose of the Study:

  • To elucidate the mechanism behind VPS34-independent autophagy.
  • To identify a role for PI(5)P in regulating autophagy and autophagosome biogenesis.

Main Methods:

  • Investigated the role of PI(5)P synthesis by PIKfyve in autophagosome biogenesis.
  • Assessed the impact of VPS34 inactivation on autophagic markers and PI(5)P levels.
  • Examined the rescue effects of PI(5)P on VPS34-deficient cells.

Main Results:

  • PI(5)P synthesis was essential for autophagosome biogenesis, increasing PI(5)P levels and stimulating autophagy.
  • VPS34 inactivation impaired autophagic precursor recruitment and autophagosome formation.
  • Exogenous PI(5)P rescued the autophagy defects in VPS34-inactivated cells.

Conclusions:

  • PI(5)P acts as a key regulator in noncanonical autophagy, potentially via PI(3)P effectors.
  • This study provides a mechanistic explanation for VPS34-independent autophagy, such as during glucose starvation.
  • Uncovered a novel cytoplasmic function for PI(5)P, expanding its known nuclear roles.

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