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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-015-1993-0) contains supplementary material, which is available to authorized users.
Highlights
In eukaryotes, the endosomal system plays a pivotal role for the sorting of endocytosed molecules and establishing which are to be reused and which ones are committed to destruction
We show that Amyloid Precursor Protein (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
In our recent study we utilised this powerful system for identifying novel interaction partners of the APP intracellular domain using mass spectrometry (Balklava et al, in press)
Summary
The endosomal system plays a pivotal role for the sorting of endocytosed molecules and establishing which are to be reused and which ones are committed to destruction. Endocytosed material is sorted in early endosomes for either recycling to the plasma membrane or retrograde transport to the trans-Golgi-network (TGN) (reviewed in [1]). As endosomes mature they acquire an increasing number of intraluminal vesicles into which cargoes destined for lysosomal degradation are sorted [2]. Late endosomes undergo fusion with lysosomes, leading to the proteolytic degradation of transmembrane proteins contained within intraluminal vesicles as well as soluble protein contained in the fluid phase late endosomes. The significance of PI(3)P is apparent when its formation is inhibited by Wortmannin which disrupts numerous endosomal sorting processes [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
