VCP/p97 modulates PtdIns3P production and autophagy initiation.

VCP/p97 is an essential multifunctional protein implicated in a plethora of intracellular quality control systems, and abnormal function of VCP is the underlying cause of several neurodegenerative disorders. We reported that VCP regulates the levels of the macroautophagy/autophagy-inducing lipid phosphatidylinositol-3-phosphate (PtdIns3P) by modulating the activity of the BECN1 (beclin 1)-containing phosphatidylinositol 3-kinase (PtdIns3K) complex. VCP stimulates the deubiquitinase activity of ATXN3 (ataxin 3) to stabilize BECN1 protein levels and also interacts with and promotes the assembly and kinase activity of the PtdIns3K complex. Acute inhibition of VCP activity impairs autophagy induction, demonstrated by a diminished PtdIns3P production and decreased recruitment of early autophagy markers WIPI2 and ATG16L1. Thus, VCP promotes autophagosome biogenesis, in addition to its previously described role in autophagosome maturation.

Keywords

ATXN3, PI(3)P, PI3K, VCP/p97, autophagy initiation, beclin 1, Autophagy, Beclin-1, Phosphatidylinositol Phosphates

Journal Title

Autophagy

Journal ISSN

1554-8627
1554-8635

Volume Title

17

Publisher

Taylor & Francis

Publisher DOI

https://doi.org/10.1080/15548627.2021.1898742

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Sponsorship

We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society) (UKDRI-2002 to DCR), The Tau Consortium, Alzheimer’s Research UK, an anonymous donation to the Cambridge Centre for Parkinson-Plus, AstraZeneca, the Swedish Natural Research Council (VR) (reference 2016–06605; to S.M.H;) and from the European Molecular Biology Organisation (EMBO long-term fellowships, ALTF 1024-2016 and ALTF 135-2016, to SMH and LW; respectively).

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