Drosophila fabp is required for light-dependent Rhodopsin-1 clearance and photoreceptor survival.
Drosophila fabp is required for light-dependent Rhodopsin-1 clearance and photoreceptor survival.
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DOI：
10.1371/journal.pgen.1009551
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发表时间：
2021-10
期刊：
影响因子：
4.5
通讯作者：
Ryoo HD
中科院分区：
文献类型：
--
作者：
Huang HW;Ryoo HD
视紫红质是一种与视网膜发色团结合的光探测蛋白，对视觉功能至关重要。巧合的是，在人类和模型生物中，视紫红质稳态失调是视网膜退化的基础。果蝇ineaEG69D突变体就是这样一个例子，其中编码的Rh1蛋白施加内质网(ER)压力，并导致光依赖性视网膜退化。这种对光的依赖的根本原因尚不清楚。在这里，我们报道了果蝇脂肪酸结合蛋白(FABP)是一个诱导NINAEG69D/+光感受器的基因，它调节光依赖视紫红质-1(Rh1)蛋白的清除和光感受器的存活。具体地说，我们在ineaEG69D/+果蝇中进行的光感受器特异性基因表达谱研究显示，FABP以及控制光依赖的Rh1蛋白降解的其他基因的表达增加。在ineaEG69D光感受器中FABP的诱导需要维生素A及其转运蛋白基因。在光下饲养的果蝇中，FABP的丢失导致了细胞质小泡中Rh1蛋白的积累。在这些条件下，Rh1水平的增加依赖于阻滞素2，后者介导了对光激活Rh1的反馈抑制。FABP突变体表现出光依赖性视网膜变性，这一表型也在其他突变体中发现，阻止光诱导的Rh1降解。这些观察揭示了光依赖的Rh1蛋白平衡和内质网应激之间先前未被发现的联系，该应激导致视网膜退化。视紫红质是一种光探测蛋白，它使用维甲酸作为发色团辅助因子。视紫红质在光感受器中受到严格的调节，因为功能失调的视紫红质会导致光感受器退化。光感受器调节视紫红质动态平衡的确切机制尚不清楚。在这里，我们报告了果蝇脂肪酸结合蛋白(FABP)是视紫红质-1(Rh1)蛋白稳态和光感受器生存所必需的基因。具体地说，我们发现Fabp是由内质网(ER)应激视紫红质-1(Rh1)突变体ineaEG69D诱导的基因之一，该突变体可用作视网膜色素变性的果蝇模型。我们进一步发现，在NINAEG69D光感受器中FABP的诱导需要维生素A及其转运蛋白基因。光感受器需要FABP来帮助降解光激活的Rh1。在没有FABP的情况下，Rh1以光依赖的方式聚集在细胞质囊泡中，并表现出光依赖的视网膜变性。这些观察表明，FABP是光诱导的Rh1降解和感光器存活所必需的。
Rhodopsins are light-detecting proteins coupled with retinal chromophores essential for visual function. Coincidentally, dysfunctional Rhodopsin homeostasis underlies retinal degeneration in humans and model organisms. Drosophila ninaEG69D mutant is one such example, where the encoded Rh1 protein imposes endoplasmic reticulum (ER) stress and causes light-dependent retinal degeneration. The underlying reason for such light-dependency remains unknown. Here, we report that Drosophila fatty acid binding protein (fabp) is a gene induced in ninaEG69D/+ photoreceptors, and regulates light-dependent Rhodopsin-1 (Rh1) protein clearance and photoreceptor survival. Specifically, our photoreceptor-specific gene expression profiling study in ninaEG69D/+ flies revealed increased expression of fabp together with other genes that control light-dependent Rh1 protein degradation. fabp induction in ninaEG69D photoreceptors required vitamin A and its transporter genes. In flies reared under light, loss of fabp caused an accumulation of Rh1 proteins in cytoplasmic vesicles. The increase in Rh1 levels under these conditions was dependent on Arrestin2 that mediates feedback inhibition of light-activated Rh1. fabp mutants exhibited light-dependent retinal degeneration, a phenotype also found in other mutants that block light-induced Rh1 degradation. These observations reveal a previously unrecognized link between light-dependent Rh1 proteostasis and the ER-stress imposing ninaEG69D mutant that cause retinal degeneration. Rhodopsins are light-detecting proteins that use retinoids as chromophore co-factors. Rhodopsins are tighly regulated in photoreceptors, as dysfunctional Rhodopsins cause photoreceptor degeneration. The precise mechanisms by which photoreceptors regulate Rhodopsin homeostasis remains unclear. Here, we report that Drosophila fatty acid binding protein (fabp) is a gene required for Rhodopsin-1 (Rh1) protein homeostasis and photoreceptor survival. Specifically, we found that fabp is among the genes induced by an endoplasmic reticulum (ER) stress-imposing Rhodopsin-1 (Rh1) mutant, ninaEG69D, which serves as a Drosophila model for Retinitis Pigmentosa. We further found that fabp induction in ninaEG69D photoreceptors required vitamin A and its transporter genes. fabp was required in photoreceptors to help degrade light-activated Rh1. In the absence of fabp, Rh1 accumulated in cytoplasmic vesicles in a light-dependent manner, and exhibited light-dependent retinal degeneration. These observations indicate that fabp is required for light-induced Rh1 degradation and photoreceptor survival.
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