Drosophila ATP6AP2/VhaPRR functions both as a novel planar cell polarity core protein and a regulator of endosomal trafficking
Drosophila ATP6AP2/VhaPRR functions both as a novel planar cell polarity core protein and a regulator of endosomal trafficking
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DOI：
10.1038/emboj.2012.323
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发表时间：
2013-01-23
期刊：
影响因子：
11.4
通讯作者：
Simons, Matias
中科院分区：
文献类型：
--
作者：
Hermle, Tobias;Guida, Maria Clara;Simons, Matias
平面细胞极性（PCP）控制细胞在组织内的取向和细胞附属物的极化生长。迄今为止，已鉴定出六种PCP核心蛋白，包括跨膜蛋白Frizzled（Fz）、Strabismus（Stbm）和Flamingo（Fmi）。这些蛋白质在上皮细胞的顶端连接处形成不对称PCP结构域。在这里，我们证明了VhaPRR，质子泵V-ATP酶的辅助亚基，直接与原钙粘蛋白FMI通过其细胞外结构域相互作用。它还显示了一个惊人的共定位与PCP蛋白在果蝇蛹翅阶段。这种定位依赖于完整的PCP结构域。然而，VhaPRR是稳定的PCP结构域所必需的，将其鉴定为新的PCP核心蛋白。VhaPRR在囊泡酸化以及内溶酶体分选和降解中发挥额外的作用。膜蛋白，如E-钙粘蛋白和Notch受体，在VhaPRR突变细胞的表面和细胞内囊泡中积累。这种运输缺陷由其他V-ATP酶亚基共享。相比之下，V-ATPase似乎在PCP调节中没有直接作用。总之，我们的研究结果表明VhaPRR的两个作用，一个是PCP，另一个是内体运输。这种双重功能确立了VhaPRR作为上皮形态发生中的关键因子。The EMBO Journal（2013）32，245-259. doi：10.1038/daj.2012.323; 2013年1月4日在线发布
Planar cell polarity (PCP) controls the orientation of cells within tissues and the polarized outgrowth of cellular appendages. So far, six PCP core proteins including the transmembrane proteins Frizzled (Fz), Strabismus (Stbm) and Flamingo (Fmi) have been identified. These proteins form asymmetric PCP domains at apical junctions of epithelial cells. Here, we demonstrate that VhaPRR, an accessory subunit of the proton pump V-ATPase, directly interacts with the protocadherin Fmi through its extracellular domain. It also shows a striking co-localization with PCP proteins during all pupal wing stages in Drosophila. This localization depends on intact PCP domains. Reversely, VhaPRR is required for stable PCP domains, identifying it as a novel PCP core protein. VhaPRR performs an additional role in vesicular acidification as well as endolysosomal sorting and degradation. Membrane proteins, such as E-Cadherin and the Notch receptor, accumulate at the surface and in intracellular vesicles of cells mutant for VhaPRR. This trafficking defect is shared by other V-ATPase subunits. By contrast, the V-ATPase does not seem to have a direct role in PCP regulation. Together, our results suggest two roles for VhaPRR, one for PCP and another in endosomal trafficking. This dual function establishes VhaPRR as a key factor in epithelial morphogenesis. The EMBO Journal (2013) 32, 245-259. doi:10.1038/emboj.2012.323; Published online 4 January 2013