PDF(Pubmed)
Abstract：
RAB28 is a farnesylated, ciliary G-protein. Patient variants in RAB28 are causative of autosomal recessive cone-rod dystrophy (CRD), an inherited human blindness. In rodent and zebrafish models, the absence of Rab28 results in diminished dawn, photoreceptor, outer segment phagocytosis (OSP). Here, we demonstrate that Rab28 is also required for dusk peaks of OSP, but not for basal OSP levels. This study further elucidated the molecular mechanisms by which Rab28 controls OSP and inherited blindness. Proteomic profiling identified factors whose expression in the eye or whose expression at dawn and dusk peaks of OSP is dysregulated by loss of Rab28. Notably, transgenic overexpression of Rab28, solely in zebrafish cones, rescues the OSP defect in rab28 KO fish, suggesting rab28 gene replacement in cone photoreceptors is sufficient to regulate Rab28-OSP. Rab28 loss also perturbs function of the visual cycle as retinoid levels of 11-cRAL, 11cRP, and atRP are significantly reduced in larval and adult rab28 KO retinae (p < .05). These data give further understanding on the molecular mechanisms of RAB28-associated CRD, highlighting roles of Rab28 in both peaks of OSP, in vitamin A metabolism and in retinoid recycling.
摘要：
RAB28是法尼基化的,纤毛G蛋白。RAB28的患者变异是常染色体隐性遗传锥杆营养不良（CRD）的原因，人类遗传的失明。在啮齿动物和斑马鱼模型中，缺少Rab28会导致黎明减弱，感光器,外节吞噬（OSP）。这里,我们证明了OSP的黄昏峰也需要Rab28，但不是基础OSP水平。这项研究进一步阐明了Rab28控制OSP和遗传性失明的分子机制。蛋白质组谱鉴定了其在眼睛中的表达或其在OSP的黎明和黄昏峰的表达因Rab28的丢失而失调的因子。值得注意的是,Rab28的转基因过表达，仅在斑马鱼视锥中，拯救了Rab28KO鱼的OSP缺陷，表明视锥光感受器中的rab28基因置换足以调节Rab28-OSP。Rab28丢失也扰乱了视觉周期的功能，因为11-cRAL的类维生素A水平，11cRP,幼虫和成年rab28KO视网膜中的atRP显着降低（p<0.05）。这些数据进一步了解了RAB28相关CRD的分子机制。突出Rab28在OSP的两个高峰中的作用，在维生素A代谢和类维生素A回收中。
