Expression of mutant CHMP2B, an ESCRT-III component involved in frontotemporal dementia, causes eye deformities due to Notch misregulation in Drosophila
Expression of mutant CHMP2B, an ESCRT-III component involved in frontotemporal dementia, causes eye deformities due to Notch misregulation in Drosophila
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DOI：
10.1096/fj.13-234138
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发表时间：
2014-02-01
期刊：
影响因子：
4.8
通讯作者：
Ahmad, S. Tariq
中科院分区：
文献类型：
--
作者：
Cheruiyot, Abigael;Lee, Jin-A;Ahmad, S. Tariq
运输所需的内体分选复合物（escrt）介导泛素化膜蛋白在多泡体中进入溶酶体进行降解。与遗传性额颞叶痴呆（FTD3）相关的CHMP2B（CHMP2B（内含子5），一种esrt - iii成分）突变破坏了内体-溶酶体途径并导致自噬体和多层结构的积累。我们之前已经证明，使用GMR-Gal4在果蝇眼中表达CHMP2B（内含子5）会导致Toll受体通路的错误调节。本研究表明，与野生型CHMP2B（CHMP2B(WT)）和CHMP2B的果蝇同源基因（CG4618）相比，使用与gmrgal4具有不同时空表达属性的驱动因素eye - gal4异位表达CHMP2B（Intron5）会导致果蝇眼睛畸形。此外，ey>CHMP2B（内含子5）果蝇在感光细胞模式和趋光行为上存在缺陷。此外，ey>CHMP2B（内含子5）果蝇在扩大的核内体中显示Notch的积累和Notch活性的上调。在ey>CHMP2B（Intron5）果蝇中，Notch活性的部分丧失显著地挽救了眼睛畸形、光感受器模式缺陷和光致行为缺陷，表明这些缺陷主要是由于Notch调控不当。这些结果表明，CHMP2B（内含子5）以细胞和发育环境依赖的方式优先影响不同的受体信号通路。Cheruiyot， A., Lee, j . -A.。高，F-B。CHMP2B是一种参与额颞叶痴呆的ESCRT-III成分，在果蝇中由于Notch调节错误导致眼睛畸形。
Endosomal sorting complexes required for transport (ESCRTs) mediate sorting of ubiquitinated membrane proteins into multivesicular bodies en route to lysosomes for degradation. A mutation in CHMP2B (CHMP2B(Intron5), an ESCRT-III component) that is associated with a hereditary form of frontotemporal dementia (FTD3) disrupts the endosomal-lysosomal pathway and causes accumulation of autophagosomes and multilamellar structures. We previously demonstrated that expression of CHMP2B(Intron5) in the Drosophila eye using GMR-Gal4 causes misregulation of the Toll receptor pathway. Here, we show that ectopic expression of CHMP2B(Intron5) using eyeless-Gal4 (ey>CHMP2B(Intron5)), a driver with different spatiotemporal expression attributes than GMR-Gal4 in the Drosophila eye, causes eye deformities when compared to expression of wild-type CHMP2B (CHMP2B(WT)) and the Drosophila homologue of CHMP2B (CG4618). In addition, ey>CHMP2B(Intron5) flies showed defects in photoreceptor cell patterning and phototactic behavior. Furthermore, ey>CHMP2B(Intron5) flies showed accumulation of Notch in enlarged endosomes and up-regulation of Notch activity. Partial loss of Notch activity in ey>CHMP2B(Intron5) flies significantly rescued eye deformities, photoreceptor patterning defect, and phototactic behavior defect, indicating that these defects are primarily due to Notch misregulation. These results demonstrate that CHMP2B(Intron5) preferentially affects different receptor signaling pathways in a cellular and developmental context-dependent manner.Cheruiyot, A., Lee, J-A., Gao, F-B., Ahmad, S. T. Expression of mutant CHMP2B, an ESCRT-III component involved in frontotemporal dementia, causes eye deformities due to Notch misregulation in Drosophila.