APP controls the formation of PI(3,5)P2 vesicles through its binding of the PIKfyve complex


Phosphoinositides are signalling lipids that are crucial for major signalling events as well as established regulators of membrane trafficking. Control of endosomal sorting and endosomal homeostasis requires phosphatidylinositol-3-phosphate (PI(3)P) and phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2), the latter a lipid of low abundance but significant physiological relevance. PI(3,5)P2 is formed by phosphorylation of PI(3)P by the PIKfyve complex which is crucial for maintaining endosomal homeostasis. Interestingly, loss of PIKfyve function results in dramatic neurodegeneration. Despite the significance of PIKfyve, its regulation is still poorly understood. Here we show that the Amyloid Precursor Protein (APP), a central molecule in Alzheimer’s disease, associates with the PIKfyve complex (consisting of Vac14, PIKfyve and Fig4) and that the APP intracellular domain directly binds purified Vac14. We also show that the closely related APP paralogues, APLP1 and 2 associate with the PIKfyve complex. Whether APP family proteins can additionally form direct protein–protein interaction with PIKfyve or Fig4 remains to be explored. We show that APP binding to the PIKfyve complex drives formation of PI(3,5)P2 positive vesicles and that APP gene family members are required for supporting PIKfyve function. Interestingly, the PIKfyve complex is required for APP trafficking, suggesting a feedback loop in which APP, by binding to and stimulating PI(3,5)P2 vesicle formation may control its own trafficking. These data suggest that altered APP processing, as observed in Alzheimer’s disease, may disrupt PI(3,5)P2 metabolism, endosomal sorting and homeostasis with important implications for our understanding of the mechanism of neurodegeneration in Alzheimer’s disease.

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Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Additional Information: © The Author(s) 2015. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Funding: Biotechnology and Biomedical Sciences Research Council (BB/ K014862/1) and Alzheimer’s Research UK (ARUK-PhD2012-13) Supplementary data avaialbe on the journal website.
Uncontrolled Keywords: endosomal sorting,ML1Nx2,mucolipin-1,neurodegeneration,TRPML1,Cell Biology,Molecular Biology,Molecular Medicine,Pharmacology,Cellular and Molecular Neuroscience
Publication ISSN: 1420-9071
Last Modified: 05 Apr 2024 07:12
Date Deposited: 10 Aug 2015 09:15
Full Text Link: http://link.spr ... 0018-015-1993-0
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2016-01
Published Online Date: 2015-07-28
Accepted Date: 2015-07-01
Authors: Currinn, Heather
Guscott, Benjamin
Balklava, Zita (ORCID Profile 0000-0001-9039-9710)
Rothnie, Alice (ORCID Profile 0000-0002-4259-7015)
Wassmer, Thomas



Version: Published Version

License: Creative Commons Attribution

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