RPGRIP1s with distinct neuronal localization and biochemical properties associate selectively with RanBP2 in amacrine neurons
RPGRIP1s with distinct neuronal localization and biochemical properties associate selectively with RanBP2 in amacrine neurons
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DOI：
10.1093/hmg/ddg202
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发表时间：
2003-08-01
影响因子：
3.5
通讯作者：
Ferreira, P
中科院分区：
文献类型：
--
作者：
Castagnet, P;Mavlyutov, T;Ferreira, P
RPGR和RPGRIP 1是在视网膜功能中具有重要作用的分子伴侣。RPGR中的突变与异质性视网膜表型有关，而RPGRIP 1中的突变导致Leber先天性黑蒙。RPGR和RPGRIP 1在不同物种的光感受器中的定位差异。这可能导致RPGR突变物种之间的表型差异。然而，它不能解释与人类RPGR和RPGRIP 1连锁突变相关的表型异质性。显示了视网膜中具有不同细胞、亚细胞定位和生化特性的RPGRIP 1同种型的存在。高质量的RPGRIP 1亚型，p175/p150，丰富的外节（OS）室的光感受器进行了鉴定。其余的亚型存在于亚细胞组分中，包括细胞核，并且是可溶的。p175/p150主要被隔离在OS和细胞核的胞浆素不溶性部分中。在选择性无长突细胞，并在转化的感光细胞系，661 W，RPGRIP 1定位在有限的病灶核孔复合物和/或附近的这些。在核孔蛋白中，RPGRIP 1同种型在体内选择性地与RanBP 2（Nup 358）结合。RPGRIP 1 s还可在661 W细胞中装饰微管，偶尔在胞体中形成卷曲样包涵体。这些结果支持不同的，但互补的功能RPGRIP 1亚型在光感受器和无长突神经元的细胞内介导的过程，并可能解释Leber表型与RPGRIP 1突变在人类。此外，这些数据暗示RanBP 2在神经（视网膜）病变的发病机制中的作用，以及作为一个对接站来介导RPGRIP 1的核质穿梭及其与无长突和661 W神经元中的其他伙伴的相互作用。
RPGR and RPGRIP1 are molecular partners with vital roles in retinal function. Mutations in RPGR are implicated in heterogeneous retinal phenotypes, while those in RPGRIP1 lead to Leber congenital amaurosis. RPGR and RPGRIP1s differentially localize in photoreceptors among species. This may contribute to phenotype disparities among species bearing mutations in RPGR. However, it cannot account for the phenotype heterogeneity associated with RPGR- and RPGRIP1-linked mutations in the human. The existence of RPGRIP1 isoforms with distinct cellular, subcellular localizations and biochemical properties in the retina is shown. High mass RPGRIP1 isoforms, p175/p150, enriched in the outer segment (OS) compartment of photoreceptors are identified. The remaining isoforms are present across subcellular fractions, including nuclei and are soluble. The p175/p150 are predominantly sequestered in the cytoskeleton-insoluble fraction of OS and nuclei. In selective amacrine cells, and in the transformed photoreceptor line, 661W, RPGRIP1s localize at restricted foci to nuclear pore complexes and/or the vicinity of these. Among the nucleoporins, RPGRIP1 isoforms selectively associate in vivo with RanBP2 (Nup358). RPGRIP1s also decorate microtubules in 661W cells and occasionally form coiled-like inclusion bodies in the perikarya. These results support distinct but complementary functions of RPGRIP1 isoforms in cytoskeletal-mediated processes in photoreceptors and amacrine neurons, and may explain the Leber phenotype linked to RPGRIP1 mutations in humans. Moreover, the data implicate a role of RanBP2 in the pathogenesis of neuro(retino)pathies and as a docking station to mediate the nucleocytoplasmic shuttling of RPGRIP1s and their interaction with other partners in amacrine and 661W neurons.