Plössl Karolina, Royer Melanie, Bernklau Sarah, Tavraz Neslihan N, Friedrich Thomas, Wild Jens, Weber Bernhard H F, Friedrich Ulrike
Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.
Institute of Chemistry, Technical University of Berlin, 10623 Berlin, Germany.
Mol Biol Cell. 2017 Aug 1;28(16):2178-2189. doi: 10.1091/mbc.E17-01-0064. Epub 2017 Jun 14.
Mutations in the gene cause X-linked juvenile retinoschisis (XLRS), a hereditary retinal dystrophy. We recently showed that retinoschisin, the protein encoded by , regulates ERK signaling and apoptosis in retinal cells. In this study, we explored an influence of retinoschisin on the functionality of the Na/K-ATPase, its interaction partner at retinal plasma membranes. We show that retinoschisin binding requires the β2-subunit of the Na/K-ATPase, whereas the α-subunit is exchangeable. Our investigations revealed no effect of retinoschisin on Na/K-ATPase-mediated ATP hydrolysis and ion transport. However, we identified an influence of retinoschisin on Na/K-ATPase-regulated signaling cascades and Na/K-ATPase localization. In addition to the known ERK deactivation, retinoschisin treatment of retinoschisin-deficient ( ) murine retinal explants decreased activation of Src, an initial transmitter in Na/K-ATPase signal transduction, and of Ca signaling marker Camk2. Immunohistochemistry on murine retinae revealed an overlap of the retinoschisin-Na/K-ATPase complex with proteins involved in Na/K-ATPase signaling, such as caveolin, phospholipase C, Src, and the IP3 receptor. Finally, retinoschisin treatment altered Na/K-ATPase localization in photoreceptors of retinae. Taken together, our results suggest a regulatory effect of retinoschisin on Na/K-ATPase signaling and localization, whereas Na/K-ATPase-dysregulation caused by retinoschisin deficiency could represent an initial step in XLRS pathogenesis.
该基因的突变会导致X连锁青少年视网膜劈裂症（XLRS），这是一种遗传性视网膜营养不良疾病。我们最近发现，由该基因编码的视网膜劈裂蛋白可调节视网膜细胞中的ERK信号传导和细胞凋亡。在本研究中，我们探讨了视网膜劈裂蛋白对Na/K-ATP酶功能的影响，Na/K-ATP酶是其在视网膜质膜上的相互作用伙伴。我们发现，视网膜劈裂蛋白的结合需要Na/K-ATP酶的β2亚基，而α亚基是可交换的。我们的研究表明，视网膜劈裂蛋白对Na/K-ATP酶介导的ATP水解和离子转运没有影响。然而，我们确定了视网膜劈裂蛋白对Na/K-ATP酶调节的信号级联反应和Na/K-ATP酶定位有影响。除了已知的ERK失活外，用视网膜劈裂蛋白处理视网膜劈裂蛋白缺陷（）的小鼠视网膜外植体，可降低Src（Na/K-ATP酶信号转导中的初始递质）和Ca信号标记物Camk2的激活。对小鼠视网膜进行免疫组织化学分析发现，视网膜劈裂蛋白-Na/K-ATP酶复合物与参与Na/K-ATP酶信号传导的蛋白质（如小窝蛋白、磷脂酶C、Src和IP3受体）存在重叠。最后，视网膜劈裂蛋白处理改变了视网膜光感受器中Na/K-ATP酶的定位。综上所述，我们的结果表明视网膜劈裂蛋白对Na/K-ATP酶信号传导和定位具有调节作用，而由视网膜劈裂蛋白缺乏引起的Na/K-ATP酶失调可能是XLRS发病机制的初始步骤。
