Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration.
Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration.
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DOI：
10.1371/journal.pgen.1009259
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发表时间：
2020-12
期刊：
影响因子：
4.5
通讯作者：
Swaroop A
中科院分区：
文献类型：
--
作者：
Hargrove-Grimes P;Mondal AK;Gumerson J;Nellissery J;Aponte AM;Gieser L;Qian H;Fariss RN;Bonifacino JS;Li T;Swaroop A
Rab-GTP 酶和相关效应子介导真核细胞内膜系统的货物运输，调节膜周转、信号转导、蛋白质回收和降解等关键过程。使用发育转录组数据，我们确定 Rabgef1（编码蛋白质 RabGEF1 或 Rabex-5）是与 Rab GTPases 相关的唯一基因，该基因与视网膜感光细胞分化表现出强烈的一致性。小鼠中 Rabgef1 的缺失（Rabgef1-/-）会导致光感受器形态缺陷，并且早在睁眼时视杆细胞和视锥细胞功能几乎完全丧失；然而，异常的外节形成只能部分解释视觉功能缺陷。视网膜感光器中的 RabGEF1 蛋白与 Rabaptin-5 相互作用，RabGEF1 缺失会导致早期内体减少，这与其他哺乳动物细胞和组织中的研究一致。电子显微镜分析显示自噬体样液泡中大分子聚集体的异常积累，以及 Rabgef1-/- 光感受器中 LC3A/B 和 p62 的免疫染色增强，这与受损的自噬一致。对发育中的 Rabgef1-/- 视网膜的转录组分析显示，与光转导、线粒体、氧化应激和内吞作用等多种途径相关的 2469 个基因的表达发生了改变，表明感光细胞死亡的早期轨迹。我们的结果表明 RabGEF1 调节的内吞和自噬途径在光感受器分化和稳态中的重要作用。我们认为 RabGEF1 和相关成分是包括视网膜病变表型在内的综合征特征的潜在候选者。内吞作用和自噬是进化上保守的过程，对于维持细胞稳态至关重要。 RabGEF1 是 Rab5-GTPase 的主要调节因子，参与胞吞作用和自噬过程中的关键步骤。我们证明，小鼠中 RabGEF1 的缺失会导致光感受器外节形成过程中的特定发育缺陷，导致早在睁眼时就出现视觉功能障碍，随后出现视网膜变性。 Rabgef1-/- 视网膜显示早期内体明显减少，以及发育中的光感受器中自噬液泡的积累。结合转录组分析，我们的研究表明了细胞事件的轨迹，包括在 RabGEF1 缺失的情况下光感受器细胞死亡之前发生的自噬改变，并确定了内吞作用和自噬在视网膜发育和蛋白质稳态中的关键作用。
Rab-GTPases and associated effectors mediate cargo transport through the endomembrane system of eukaryotic cells, regulating key processes such as membrane turnover, signal transduction, protein recycling and degradation. Using developmental transcriptome data, we identified Rabgef1 (encoding the protein RabGEF1 or Rabex-5) as the only gene associated with Rab GTPases that exhibited strong concordance with retinal photoreceptor differentiation. Loss of Rabgef1 in mice (Rabgef1-/-) resulted in defects specifically of photoreceptor morphology and almost complete loss of both rod and cone function as early as eye opening; however, aberrant outer segment formation could only partly account for visual function deficits. RabGEF1 protein in retinal photoreceptors interacts with Rabaptin-5, and RabGEF1 absence leads to reduction of early endosomes consistent with studies in other mammalian cells and tissues. Electron microscopy analyses reveal abnormal accumulation of macromolecular aggregates in autophagosome-like vacuoles and enhanced immunostaining for LC3A/B and p62 in Rabgef1-/- photoreceptors, consistent with compromised autophagy. Transcriptome analysis of the developing Rabgef1-/- retina reveals altered expression of 2469 genes related to multiple pathways including phototransduction, mitochondria, oxidative stress and endocytosis, suggesting an early trajectory of photoreceptor cell death. Our results implicate an essential role of the RabGEF1-modulated endocytic and autophagic pathways in photoreceptor differentiation and homeostasis. We propose that RabGEF1 and associated components are potential candidates for syndromic traits that include a retinopathy phenotype. Endocytosis and autophagy are evolutionarily conserved processes that are essential for maintenance of cellular homeostasis. RabGEF1 is a major regulator of the Rab5-GTPase, which participates in key steps during endocytosis and autophagy. We demonstrate that loss of RabGEF1 in mice causes specific developmental defects during photoreceptor outer segment formation, leading to visual dysfunction as early as eye opening followed by retinal degeneration. Rabgef1-/- retina shows a clear reduction in early endosomes as well as accumulation of autophagic vacuoles in developing photoreceptors. Together with transcriptome analysis, our studies suggest a trajectory of cellular events including altered autophagy that precede photoreceptor cell death in the absence of RabGEF1 and establish a critical role of endocytosis and autophagy in retinal development and proteostasis.
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影响因子：
7.2
作者：
Bujakowska KM;Liu Q;Pierce EA
通讯作者：
Pierce EA
影响因子：
64.5
作者：
Horiuchi, H;Lippe, R;Zerial, M
通讯作者：
Zerial, M
影响因子：
3.5
作者：
Estrada-Cuzcano, Alejandro;Roepman, Ronald;Mans, Dorus A.
通讯作者：
Mans, Dorus A.
DOI：
10.1073/pnas.0508214103
发表时间：
2006-03-07
影响因子：
11.1
作者：
Akimoto, M;Cheng, H;Swaroop, A
通讯作者：
Swaroop, A
影响因子：
5.9
作者：
Brooks, Matthew J.;Chen, Holly Y.;Swaroop, Anand
通讯作者：
Swaroop, Anand