Satoh Akiko K, Ready Donald F
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
Curr Biol. 2005 Oct 11;15(19):1722-33. doi: 10.1016/j.cub.2005.08.064.
Arrestins are pivotal, multifunctional organizers of cell responses to GPCR stimulation, including cell survival and cell death. In Drosophila norpA and rdgC mutants, endocytosis of abnormally stable complexes of rhodopsin (Rh1) and fly photoreceptor Arrestin2 (Arr2) triggers cell death, implicating Rh1/Arr2-bearing endosomes in pro-cell death signaling, potentially via arrestin-mediated GPCR activation of effector kinase pathways. In order to further investigate arrestin function in photoreceptor physiology and survival, we studied Arr2's partner photoreceptor arrestin, Arr1, in developing and adult Drosophila compound eyes.
We report that Arr1, but not Arr2, is essential for normal, light-induced rhodopsin endocytosis. Also distinct from Arr2, Arr1 is essential for light-independent photoreceptor survival. Photoreceptor cell death caused by loss of Arr1 is strongly suppressed by coordinate loss of Arr2. We further find that Rh1 C-terminal phosphorylation is essential for light-induced endocytosis and also for translocation of Arr1, but not Arr2, from dark-adapted photoreceptor cytoplasm to photosensory membrane rhabdomeres. In contrast to a previous report, we do not find a requirement for photoreceptor myosin kinase NINAC in Arr1 or Arr2 translocation.
The two Drosophila photoreceptor arrestins mediate distinct and essential cell pathways downstream of rhodopsin activation. We propose that Arr1 mediates an endocytotic cell-survival activity, scavenging phosphorylated rhodopsin and thereby countering toxic Arr2/Rh1 accumulation; elimination of toxic Arr2/Rh1 in double mutants could thus rescue arr1 mutant photoreceptor degeneration.
抑制蛋白是细胞对G蛋白偶联受体（GPCR）刺激反应的关键多功能组织者，包括细胞存活和细胞死亡。在果蝇norpA和rdgC突变体中，视紫红质（Rh1）与果蝇光感受器抑制蛋白2（Arr2）异常稳定复合物的内吞作用会引发细胞死亡，这表明携带Rh1/Arr2的内体参与了促细胞死亡信号传导，可能是通过抑制蛋白介导的效应激酶途径的GPCR激活。为了进一步研究抑制蛋白在光感受器生理和存活中的功能，我们在发育中和成年果蝇复眼中研究了Arr2的伙伴光感受器抑制蛋白Arr1。
我们报告称，Arr1而非Arr2对于正常的光诱导视紫红质内吞作用至关重要。与Arr2也不同的是，Arr1对于不依赖光的光感受器存活至关重要。Arr1缺失导致的光感受器细胞死亡会因Arr2的协同缺失而受到强烈抑制。我们进一步发现，Rh1的C末端磷酸化对于光诱导内吞作用以及Arr1从暗适应的光感受器细胞质向光感膜微绒毛的转运至关重要，但对Arr2的转运并非如此。与之前的一份报告相反，我们没有发现光感受器肌球蛋白激酶NINAC在Arr1或Arr2转运中的需求。
两种果蝇光感受器抑制蛋白介导视紫红质激活下游不同且必不可少的细胞途径。我们提出，Arr1介导一种内吞性细胞存活活性，清除磷酸化的视紫红质，从而对抗有毒的Arr2/Rh1积累；因此，双突变体中有毒的Arr2/Rh1的消除可以挽救arr1突变体光感受器的退化。
