The Zn2+ transporter ZIP7 enhances endoplasmic-reticulum-associated protein degradation and prevents neurodegeneration in Drosophila

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

doi:10.1016/j.devcel.2024.04.003

The Zn²⁺ transporter ZIP7 enhances endoplasmic-reticulum-associated protein degradation and prevents neurodegeneration in Drosophila

Dev Cell. 2024 Apr 22:S1534-5807(24)00228-4. doi: 10.1016/j.devcel.2024.04.003. Online ahead of print.

Authors

Affiliations

¹ Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93110, USA.
² 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. Electronic address: wei_dai@fudan.edu.cn.
³ Molecular, Cellular, and Developmental Biology Department, University of California, Santa Barbara, CA 93110, USA. Electronic address: dmontell@ucsb.edu.

PMID: 38670102
DOI: 10.1016/j.devcel.2024.04.003

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.

Keywords: Drosophila; ER stress; ERAD; apoptosis; border cell migration; integrated stress response; neurodegeneration; proteasome; retinitis pigmentosa; zinc transport.