Year: 2023
Type: preprint
Abstract: 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 2+ transporter ZIP7 causes ER stress, however the mechanism is unknown. Here we show that ZIP7 enhances ERAD and that cytosolic Zn 2+ is limiting for deubiquitination of client proteins by the Rpn11 Zn 2+ 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. One-Sentence Summary Zn 2+ transport from the ER to the cytosol promotes deubiquitination and proteasomal degradation of misfolded proteins and prevents blindness in a fly neurodegeneration model.
Authors: Xiaoran Guo, Morgan Mutch, Alba Yurani Torres, Maddalena Nano, Drew McDonald, Zijing Chen, Craig Montell, Wei Dai, Denise J. Montell
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4377822698