Zinc-redox crosstalk regulates proteostasis in the endoplasmic reticulum

Zinc homeostasis is crucial for various biological processes, including gene regulation, signal transduction, and proteostasis. ZIP7 is a membrane transporter that exports zinc ions (Zn2+) from the lumen of the endoplasmic reticulum (ER) to the cytosol, and its dysfunction causes ER stress, although the underlying mechanism remains unclear. Here, we show that ZIP7 inhibition increases the labile Zn2+ concentration in the ER to micromolar levels, approximately 106 times higher than its steady-state level. Such abnormally high Zn2+ concentrations disrupt the function and trafficking of the Zn2+-dependent chaperone ERp44 at the ER-Golgi interface. In vitro assays using recombinant proteins demonstrated that Zn2+ inhibits the Ero1α-PDI oxidative system, and that ERp44 enhances this inhibitory effect. Consequently, the ER redox environment becomes more reducing, severely impairing the oxidative folding of key membrane receptors such as Notch1 and EGFR. These findings reveal the essential role of zinc homeostasis in redox-dependent proteostasis within the ER. This study demonstrates a close interplay between zinc and redox homeostasis in the ER. Aberrant zinc elevation disrupts ERp44-mediated protein quality control and impairs oxidative folding of key membrane receptors, including EGFR and Notch.