Abstract

Zinc homeostasis is a highly regulated process in mammalian cells that is critical for normal growth and development. Movement of zinc across cell compartments is controlled by two classes of transporters: Slc39a family members transport zinc into the cytosol from either the extracellular space or intracellular stores such as the endoplasmic reticulum (ER), whereas the SLC30A family mediates zinc efflux from the cytosol. In this study, we report that genetic ablation of SLC39A7 (ZIP7) results in decreased cytosolic zinc levels, increased ER zinc levels, impaired cell proliferation, and induction of ER stress. Confirmatory of impaired zinc transport as the causal mechanism, both the increased ER stress and impaired cell proliferation were rescued by increasing cytosolic zinc. Furthermore, using these robust cellular phenotypes, we implemented a small-molecule library screen with 2800 compounds and identified one small molecule capable of rescuing ER stress and cell proliferation in ZIP7-deficient cells in the low micromolar range.