Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93110, USA.
Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93110, USA; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
Dev Cell. 2024 Jul 8;59(13):1655-1667.e6. doi: 10.1016/j.devcel.2024.04.003. Epub 2024 Apr 25.
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 Zn 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 Zn transport enhances the obligatory deubiquitination of proteins by the Rpn11 Zn metalloproteinase in the proteasome lid. In human cells, ZIP7 and Zn 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 Zn transport is a previously unknown, rate-limiting step for ERAD in vivo with therapeutic potential in protein misfolding diseases.
蛋白毒性应激会引发许多退行性疾病。细胞最初通过激活未折叠蛋白反应（UPR），包括内质网相关蛋白降解（ERAD），来适应错误折叠的蛋白质。然而，持续的应激会引发细胞凋亡。增强 ERAD 是治疗蛋白质错误折叠疾病的一种有前途的方法。ER 定位的 Zn 转运蛋白 ZIP7 从植物到人类都是保守的，对于肠道自我更新、Notch 信号、细胞迁移和存活都是必需的。然而，这些不同表型的统一机制尚不清楚。在研究果蝇边界细胞迁移时，我们发现 ZIP7 介导的 Zn 转运增强了 Rpn11 Zn 金属蛋白酶在蛋白酶体盖中的必需去泛素化作用。在人类细胞中，ZIP7 和 Zn 是去泛素化的限制因素。在由错误折叠的视紫红质（Rh1）引起的果蝇神经退行性变模型中，ZIP7 的过表达降解了错误折叠的 Rh1，并挽救了感光器的存活和果蝇的视力。因此，ZIP7 介导的 Zn 转运是体内 ERAD 的一个以前未知的限速步骤，在蛋白质错误折叠疾病的治疗中有潜在的应用价值。
