Zinc regulates ERp44-dependent protein quality control in the early secretory pathway

Zinc ions (Zn(2+)) are imported into the early secretory pathway by Golgi-resident transporters, but their handling and functions are not fully understood. Here, we show that Zn(2+) binds with high affinity to the pH-sensitive chaperone ERp44, modulating its localization and ability to retrieve clients like Ero1α and ERAP1 to the endoplasmic reticulum (ER). Silencing the Zn(2+) transporters that uptake Zn(2+) into the Golgi led to ERp44 dysfunction and increased secretion of Ero1α and ERAP1. High-resolution crystal structures of Zn(2+)-bound ERp44 reveal that Zn(2+) binds to a conserved histidine-cluster. The consequent large displacements of the regulatory C-terminal tail expose the substrate-binding surface and RDEL motif, ensuring client capture and retrieval. ERp44 also forms Zn(2+)-bridged homodimers, which dissociate upon client binding. Histidine mutations in the Zn(2+)-binding sites compromise ERp44 activity and localization. Our findings reveal a role of Zn(2+) as a key regulator of protein quality control at the ER-Golgi interface.