Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, 75015 Paris, France.
Graduate Program GRK1104, University of Freiburg, 79106 Freiburg, Germany.
Mol Biol Cell. 2018 Sep 1;29(18):2156-2164. doi: 10.1091/mbc.E18-04-0234. Epub 2018 Jul 11.
ATP6AP2 (also known as the [pro]renin receptor) is a type I transmembrane protein that can be cleaved into two fragments in the Golgi apparatus. While in Drosophila ATP6AP2 functions in the planar cell polarity (PCP) pathway, recent human genetic studies have suggested that ATP6AP2 could participate in the assembly of the V-ATPase in the endoplasmic reticulum (ER). Using a yeast model, we show here that the V-ATPase assembly factor Voa1 can functionally be replaced by Drosophila ATP6AP2. This rescue is even more efficient when coexpressing its binding partner ATP6AP1, indicating that these two proteins together fulfill Voa1 functions in higher organisms. Structure-function analyses in both yeast and Drosophila show that proteolytic cleavage is dispensable, while C-terminus-dependent ER retrieval is required for ATP6AP2 function. Accordingly, we demonstrate that both overexpression and lack of ATP6AP2 causes ER stress in Drosophila wing cells and that the induction of ER stress is sufficient to cause PCP phenotypes. In summary, our results suggest that full-length ATP6AP2 contributes to the assembly of the V-ATPase proton pore and that impairment of this function affects ER homeostasis and PCP signaling.
ATP6AP2（也称为[前]肾素受体）是一种 I 型跨膜蛋白，可在高尔基体中切割成两个片段。虽然在果蝇中 ATP6AP2 参与平面细胞极性（PCP）途径，但最近的人类遗传学研究表明 ATP6AP2 可能参与内质网（ER）中 V-ATPase 的组装。在这里，我们使用酵母模型表明，V-ATPase 组装因子 Voa1 可以被果蝇 ATP6AP2 替代。当共同表达其结合伴侣 ATP6AP1 时，这种挽救作用甚至更有效，表明这两种蛋白质一起在高等生物中发挥 Voa1 的功能。酵母和果蝇中的结构功能分析表明，蛋白水解切割是可有可无的，而 C 端依赖性 ER 回收对于 ATP6AP2 功能是必需的。因此，我们证明在果蝇翅膀细胞中，ATP6AP2 的过表达和缺乏都会导致 ER 应激，而 ER 应激的诱导足以引起 PCP 表型。总之，我们的结果表明全长 ATP6AP2 有助于 V-ATPase 质子孔的组装，并且该功能的损害会影响 ER 稳态和 PCP 信号转导。
