title: APP controls the formation of PI(3,5)P(2) vesicles through its binding of the PIKfyve complex.
abstract: 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.
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Currinn
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Guscott
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
authors.forename: Zita
authors.initials: Z
authors.lastname: Balklava
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Rothnie
authors.affiliation: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK. t.wassmer@aston.ac.uk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wassmer
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D011485:Protein Binding; D060066:Protein Interaction Maps; D021381:Protein Transport
chemical_list: C489697:APLP1 protein, human; C084104:APLP2 protein, human; C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate; D019869:Phosphatidylinositol 3-Kinases; C492139:PIKFYVE protein, human
keywords: Endosomal sorting; ML1Nx2; Mucolipin-1; Neurodegeneration; TRPML1