ZnT4 transports zinc to critical zinc‐dependent proteins in the trans‐Golgi network and exports Zn across the cell membrane in mammary epithelial cells

The benefits of breastfeeding include optimized growth, neurological development and immune function in infants. However, sub‐optimal lactation occurs in ~15% of women and results in reduced milk volume, compromised milk composition or lactation failure. A mutation in the gene encoding ZnT4 (SLC30A4) is associated with sub‐optimal lactation in mice. These mice have smaller mammary glands (MG), decreased milk synthesis and ~35% less Zn secreted into milk. We hypothesized that ZnT4 plays a critical role in MG function. Genetic manipulation of ZnT4 abundance in mammary epithelial cells was positively correlated with Zn secretion. ZnT4 transported Zn into a labile Zn pool in the trans‐Golgi network (TGN) where it was made available for Zn‐dependent proteins. This was evidenced by ZnT4 attenuation which decreased carbonic anhydrase VI expression, and ZnT4 over‐expression which decreased galactosyltransferase activity. Additionally, ZnT4 exported Zn directly across the cell membrane. In summary, ZnT4 has a dual role involving 1) labile Zn accumulation in the TGN providing Zn to Zn‐dependent proteins; and 2) Zn transport across the cell membrane into milk. Our studies suggest that ZnT4 provides Zn to proteins critical for secretion and mammary gland function, thus understanding factors that regulate ZnT4 is important to increasing the incidence of lactation and improving the health of women and children. Grant Funding Source : NIH R01 HD058614