Zinc supply mediated by ZNT5-ZNT6 and ZNT7 is critical to glycosylphosphatidylinositol-anchored protein expression

Glycosylphosphatidylinositol (GPI)-anchored proteins play crucial roles in various enzyme activities, cell signaling and adhesion, and immune responses. ZNT type zinc transporter proteins mobilize cytosolic zinc to the extracellular space and intracellular compartments. Here, we report that the early secretory pathway ZNTs [ZNT5-ZNT6 heterodimers (ZNT5-6) and ZNT7 homodimers (ZNT7)], which supply zinc into the lumen of organelles, are essential for GPI-anchored protein expression on the cell surface. Loss of ZNT5-6 and ZNT7 zinc transport functions results in a significant reduction of GPI-anchored proteins similar to that of mutant cells lacking phosphatidylinositol glycan anchor biosynthesis (PIG) genes. Disrupted ZNT5 and ZNT7 genes in medaka fish show touch-insensitive phenotypes similar to those of zebrafish PIG mutants. These findings provide a previously unappreciated insight into the regulation of GPI-anchored protein expression and of protein quality control in the early secretory pathway.