APP controls the formation of PI(3,5)P(2) vesicles through its binding of the PIKfyve complex.
APP controls the formation of PI(3,5)P(2) vesicles through its binding of the PIKfyve complex.
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DOI：
10.1007/s00018-015-1993-0
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Wassmer T
中科院分区：
文献类型：
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作者：
Currinn H;Guscott B;Balklava Z;Rothnie A;Wassmer T
磷脂酰肌醇是一种信号转导脂类物质，对于重大信号转导事件以及膜运输的既定调节机制都是至关重要的。控制内体分选和内体动态平衡需要磷脂酰肌醇-3-磷酸(PI(3)P)和磷脂酰肌醇-3，5-二磷酸(PI(3，5)P2)，后者是一种低丰度但具有显著生理相关性的脂质。PI(3，5)P2是由PIKfyve复合体对PI(3)P的磷酸化而形成的，PIKfyve复合体对维持内体内环境的稳定至关重要。有趣的是，PIKfyve功能的丧失会导致戏剧性的神经退化。尽管PIKfyve意义重大，但人们对其监管仍知之甚少。在这里，我们证明了淀粉样前体蛋白(APP)是阿尔茨海默病的中心分子，与PIKfyve复合体(由Vac14、PIKfyve和图4组成)有关，并且APP细胞内结构域直接与纯化的Vac14结合。我们还表明，密切相关的APP类似物APLP1和APL2与PIKfyve复合体有关。APP家族蛋白是否还能与PIKfyve或Fig4形成直接的蛋白质-蛋白质相互作用还有待探索。我们证明了APP与PIKfyve复合体的结合驱动PI(3，5)P2阳性囊泡的形成，并且APP基因家族成员是支持PIKfyve功能所必需的。有趣的是，PIKfyve复合体是APP运输所必需的，这表明APP通过与PI(3，5)P2囊泡形成结合并刺激其形成来控制其自身的运输。这些数据表明，正如在阿尔茨海默病中观察到的那样，APP处理的改变可能会扰乱PI(3，5)P2的代谢、内体分类和动态平衡，这对我们理解阿尔茨海默病的神经退变机制具有重要意义。本文的在线版本(doi：10.1007/s000180151993-0)包含补充材料，授权用户可以使用。
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. The online version of this article (doi:10.1007/s00018-015-1993-0) contains supplementary material, which is available to authorized users.