PI(5)P Regulates Autophagosome Biogenesis
Korolchuk, Viktor I
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Vicinanza, M., Korolchuk, V. I., Ashkenazi, A., Puri, C., Menzies, F., Clarke, J., & Rubinsztein, D. (2015). PI(5)P Regulates Autophagosome Biogenesis. Molecular Cell, 57 219-234. https://doi.org/10.1016/j.molcel.2014.12.007
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.
We are grateful for funding from a Wellcome Trust Principal Research Fellowship (095317/Z/11/Z to D.C.R.), a Wellcome Trust Strategic Award (100140/Z/ 12/Z), the NIHR Biomedical Research Centre in Dementia at Addenbrooke’s Hospital, an MRC Confidence in Concepts grant (D.C.R.), and a FEBS Long- Term Fellowship (A.A.).
Wellcome Trust (095317/Z/11/Z)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (095317/Z/11/A)
External DOI: https://doi.org/10.1016/j.molcel.2014.12.007
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246804
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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