Guo, X., Mutch, M., Torres, A.Y., Nano, M., Rauth, N., Harwood, J., McDonald, D., Chen, Z., Montell, C., Dai, W., Montell, D.J. (2024). The Zn[2+] transporter ZIP7 enhances endoplasmic-reticulum-associated protein degradation and prevents neurodegeneration in Drosophila.  Dev. Cell 59(13): 1655--1667.e6.

FBrf0260002

Research paper

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[2+] 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[2+] transport enhances the obligatory deubiquitination of proteins by the Rpn11 Zn[2+] metalloproteinase in the proteasome lid. In human cells, ZIP7 and Zn[2+] 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[2+] transport is a previously unknown, rate-limiting step for ERAD in vivo with therapeutic potential in protein misfolding diseases.

PMC11233247 (PMC) (EuropePMC)