Disturbances in protein phase transitions promote protein aggregation─a neurodegeneration hallmark. The modular Ran-binding protein 2 (Ranbp2) is a cytosolic molecular hub for rate-limiting steps of phase transitions of Ran-GTP-bound protein ensembles exiting nuclear pores. Chaperones also regulate phase transitions and proteostasis by suppressing protein aggregation. Ranbp2 haploinsufficiency promotes the age-dependent neuroprotection of the chorioretina against phototoxicity by proteostatic regulations of neuroprotective substrates of Ranbp2 and by suppressing the buildup of polyubiquitylated substrates. Losses of peptidyl-prolyl cis–trans isomerase (PPIase) and chaperone activities of the cyclophilin domain (CY) of Ranbp2 recapitulate molecular effects of Ranbp2 haploinsufficiency. These CY impairments also stimulate deubiquitylation activities and phase transitions of 19S cap subunits of the 26S proteasome that associates with Ranbp2. However, links between CY moonlighting activity, substrate ubiquitylation, and proteostasis remain incomplete. Here, we reveal the Ranbp2 regulation of small heat shock chaperones─crystallins in the chorioretina by proteomics of mice with total or selective modular deficits of Ranbp2. Specifically, loss of CY PPIase of Ranbp2 upregulates αA-Crystallin, which is repressed in adult nonlenticular tissues. Conversely, impairment of CY’s chaperone activity opposite to the PPIase pocket downregulates a subset of αA-Crystallin’s substrates, γ-crystallins. These CY-dependent effects cause age-dependent and chorioretinal-selective declines of ubiquitylated substrates without affecting the chorioretinal morphology. A model emerges whereby inhibition of Ranbp2’s CY PPIase remodels crystallins’ expressions, subdues molecular aging, and preordains the chorioretina to neuroprotection by augmenting the chaperone capacity and the degradation of polyubiquitylated substrates against proteostatic impairments. Further, the druggable Ranbp2 CY holds pan-therapeutic potential against proteotoxicity and neurodegeneration.

中文翻译：

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小热休克伴侣的蛋白质静态重塑 — Ran 结合蛋白 2 的晶状体蛋白 — 以及肽基脯氨酰顺反异构酶及其亲环蛋白结构域的伴侣活性


蛋白质相变的干扰会促进蛋白质聚集——这是神经退行性变的标志。模块化 Ran 结合蛋白 2 (Ranbp2) 是细胞质分子中心，用于限制 Ran-GTP 结合蛋白整体离开核孔的相变步骤。伴侣还通过抑制蛋白质聚集来调节相变和蛋白质稳态。 Ranbp2 单倍体不足通过 Ranbp2 神经保护底物的蛋白抑制调节和抑制多泛素化底物的积累，促进脉络膜视网膜针对光毒性的年龄依赖性神经保护。 Ranbp2 肽基脯氨酰顺反异构酶 (PPIase) 和亲环蛋白结构域 (CY) 伴侣活性的丧失概括了 Ranbp2 单倍体不足的分子效应。这些 CY 损伤还会刺激与 Ranbp2 相关的 26S 蛋白酶体的 19S 帽亚基的去泛素化活性和相变。然而，CY 兼职活动、底物泛素化和蛋白质稳态之间的联系仍然不完整。在这里，我们通过对 Ranbp2 完全或选择性模块缺陷的小鼠进行蛋白质组学研究，揭示了 Ranbp2 对脉络膜视网膜中的小热休克伴侣——晶状体蛋白的调节。具体来说，Ranbp2 的 CY PPIase 缺失会上调 αA-Crystallin，而αA-Crystallin 在成人非豆状组织中受到抑制。相反，与 PPIase 口袋相反的 CY 伴侣活性受损会下调 αA-晶状体蛋白底物 γ-晶状体蛋白的子集。这些 CY 依赖性效应导致泛素化底物的年龄依赖性和脉络膜视网膜选择性下降，而不影响脉络膜视网膜形态。 出现了一个模型，通过抑制 Ranbp2 的 CY PPIase 可以重塑晶状体蛋白的表达，抑制分子衰老，并通过增强伴侣能力和多泛素化底物的降解来对抗蛋白质稳态损伤，从而预先确定脉络膜视网膜的神经保护作用。此外，可药物化的 Ranbp2 CY 具有针对蛋白质毒性和神经退行性变的泛治疗潜力。