Browse by author
Lookup NU author(s): Professor Viktor KorolchukORCiD, Fiona Menzies
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Vicinanza M, Korolchuk VI, Ashkenazi A, Puri C, Menzies FM, Clarke JH, Rubinsztein DC
Publication type: Article
Publication status: Published
Journal: Molecular Cell
Year: 2015
Volume: 57
Issue: 2
Pages: 219-234
Print publication date: 22/01/2015
Online publication date: 08/01/2015
Acceptance date: 25/11/2014
Date deposited: 02/03/2016
ISSN (print): 1097-2765
ISSN (electronic): 1097-4164
Publisher: Cell Press
URL: http://dx.doi.org/10.1016/j.molcel.2014.12.007
DOI: 10.1016/j.molcel.2014.12.007
PubMed id: 25578879
Notes: Open Access License CC-BY (OA Wellcome Trust Funded)
Altmetrics provided by Altmetric