Rescue of proteotoxic stress and neurodegeneration by the Zn2+ transporter ZIP7

Xiaoran Guo; Morgan Mutch; Alba Yurani Torres; Maddalena Nano; Drew McDonald; Zijing Chen; Craig Montell; Wei Dai; Denise J Montell

doi:10.1101/2023.05.22.541645

Rescue of proteotoxic stress and neurodegeneration by the Zn²⁺ transporter ZIP7

bioRxiv [Preprint]. 2023 May 22:2023.05.22.541645. doi: 10.1101/2023.05.22.541645.

Authors

Xiaoran Guo^{1

2}, Morgan Mutch¹, Alba Yurani Torres¹, Maddalena Nano¹, Drew McDonald¹, Zijing Chen¹, Craig Montell¹, Wei Dai^{1

3}, Denise J Montell¹

Affiliations

¹ Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93110.
² present address: Biochemistry Department, Stanford University, Stanford, CA 94305.
³ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.

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 Zn²⁺ transporter ZIP7 causes ER stress, however the mechanism is unknown. Here we show that ZIP7 enhances ERAD and that cytosolic Zn²⁺ is limiting for deubiquitination of client proteins by the Rpn11 Zn²⁺ 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.

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Abstract

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