Guo Xiaoran, Mutch Morgan, Torres Alba Yurani, Nano Maddalena, McDonald Drew, Chen Zijing, Montell Craig, Dai Wei, Montell Denise J
Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93110.
present address: Biochemistry Department, Stanford University, Stanford, CA 94305.
bioRxiv. 2023 May 22:2023.05.22.541645. doi: 10.1101/2023.05.22.541645.
Proteotoxic stress drives numerous degenerative diseases. In response to misfolded proteins, cells adapt 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. From plants to humans, loss of the Zn transporter ZIP7 causes ER stress, however the mechanism is unknown. Here we show that ZIP7 enhances ERAD and that cytosolic Zn is limiting for deubiquitination of client proteins by the Rpn11 Zn metalloproteinase as they enter the proteasome in Drosophila and human cells. ZIP7 overexpression rescues defective vision caused by misfolded rhodopsin in Drosophila. Thus ZIP7 overexpression may prevent diseases caused by proteotoxic stress, and existing ZIP inhibitors may be effective against proteasome-dependent cancers.
蛋白毒性应激引发多种退行性疾病。作为对错误折叠蛋白的反应，细胞通过激活未折叠蛋白反应（UPR）来适应，包括内质网相关蛋白降解（ERAD）。然而，持续的应激会触发细胞凋亡。增强ERAD是治疗蛋白错误折叠疾病的一种有前景的方法。从植物到人类，锌转运蛋白ZIP7的缺失都会导致内质网应激，但其机制尚不清楚。在这里，我们表明ZIP7增强了ERAD，并且在果蝇和人类细胞中，当客户蛋白进入蛋白酶体时，胞质锌对于Rpn11锌金属蛋白酶对其进行去泛素化作用是有限的。ZIP7的过表达挽救了果蝇中由错误折叠的视紫红质引起的视力缺陷。因此，ZIP7的过表达可能预防由蛋白毒性应激引起的疾病，并且现有的ZIP抑制剂可能对蛋白酶体依赖性癌症有效。
