Department of Oral Biology, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Department of Pharmacology, Brain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
Cell Rep. 2015 Dec 29;13(12):2808-16. doi: 10.1016/j.celrep.2015.12.009.
Cilia are highly specialized antennae-like cellular organelles. Inositol polyphosphate 5-phosphatase E (INPP5E) converts PI(4,5)P2 into PI4P and is required for proper ciliary function. Although Inpp5e mutations are associated with ciliopathies in humans and mice, the precise molecular role INPP5E plays in cilia remains unclear. Here, we report that Drosophila INPP5E (dINPP5E) regulates ciliary protein trafficking by controlling the phosphoinositide composition of ciliary membranes. Mutations in dInpp5e lead to hearing deficits due to the mislocalization of dTULP and mechanotransduction channels, Inactive and NOMPC, in chordotonal cilia. Both loss of dINPP5E and ectopic expression of the phosphatidylinositol-4-phosphate 5-kinase Skittles increase PI(4,5)P2 levels in the ciliary base. The fact that Skittles expression phenocopies the dInpp5e mutants confirms a central role for PI(4,5)P2 in the regulation of dTULP, Inactive, and NOMPC localization. These data suggest that the spatial localization and levels of PI(4,5)P2 in ciliary membranes are important regulators of ciliary trafficking and function.
纤毛是高度特化的天线状细胞细胞器。肌醇多磷酸 5-磷酸酶 E（INPP5E）将 PI(4,5)P2 转化为 PI4P，是正常纤毛功能所必需的。尽管 INPP5E 突变与人类和小鼠的纤毛病有关，但 INPP5E 在纤毛中的精确分子作用仍不清楚。在这里，我们报告果蝇 INPP5E（dINPP5E）通过控制纤毛膜的磷酸肌醇组成来调节纤毛蛋白的运输。dInpp5e 突变导致听觉缺陷，这是由于 dTULP 和机械转导通道 Inactive 和 NOMPC 在听毛纤毛中的定位错误。dINPP5E 的缺失和 Skittles（一种磷脂酰肌醇-4-磷酸 5-激酶）的异位表达都会增加纤毛基部的 PI(4,5)P2 水平。Skittles 表达可模拟 dInpp5e 突变体这一事实证实了 PI(4,5)P2 在调节 dTULP、Inactive 和 NOMPC 定位中的核心作用。这些数据表明，纤毛膜中 PI(4,5)P2 的空间定位和水平是纤毛运输和功能的重要调节剂。
