PDF(Pubmed)
Abstract：
Proteotoxic stress drives numerous degenerative diseases. Cells initially adapt to misfolded proteins by activating the unfolded protein response (UPR), including endoplasmic-reticulum-associated protein degradation (ERAD). However, persistent stress triggers apoptosis. Enhancing ERAD is a promising therapeutic approach for protein misfolding diseases. The ER-localized Zn2+ transporter ZIP7 is conserved from plants to humans and required for intestinal self-renewal, Notch signaling, cell motility, and survival. However, a unifying mechanism underlying these diverse phenotypes was unknown. In studying Drosophila border cell migration, we discovered that ZIP7-mediated Zn2+ transport enhances the obligatory deubiquitination of proteins by the Rpn11 Zn2+ metalloproteinase in the proteasome lid. In human cells, ZIP7 and Zn2+ are limiting for deubiquitination. In a Drosophila model of neurodegeneration caused by misfolded rhodopsin (Rh1), ZIP7 overexpression degrades misfolded Rh1 and rescues photoreceptor viability and fly vision. Thus, ZIP7-mediated Zn2+ transport is a previously unknown, rate-limiting step for ERAD in vivo with therapeutic potential in protein misfolding diseases.
摘要：
蛋白质毒性应激驱动许多退行性疾病。细胞最初通过激活未折叠的蛋白质反应（UPR）来适应错误折叠的蛋白质，包括内质网相关蛋白降解(ERAD)。然而,持续的压力触发细胞凋亡。增强ERAD是蛋白质错误折叠疾病的有希望的治疗方法。ER定位的Zn2转运蛋白ZIP7从植物到人类是保守的，并且是肠道自我更新所必需的，陷波信号,细胞运动性,和生存。然而,这些不同表型的统一机制尚不清楚.在研究果蝇边缘细胞迁移时，我们发现ZIP7介导的Zn2+转运通过蛋白酶体盖中的Rpn11Zn2+金属蛋白酶增强蛋白质的强制性去泛素化。在人类细胞中，ZIP7和Zn2+限制了去泛素化。在由错误折叠的视紫红质（Rh1）引起的果蝇神经变性模型中，ZIP7过表达降解错误折叠的Rh1并挽救光感受器活力和飞行视力。因此，ZIP7介导的Zn2+转运是以前未知的，在蛋白质错误折叠疾病中具有治疗潜力的体内ERAD的限速步骤。
