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PI(5)P regulates autophagosome biogenesis

Lookup NU author(s): Dr Viktor Korolchuk, Fiona Menzies

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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)


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