The regulation of the activation in BCR signaling by ZIP9 transporter

Zinc is the essential trace element and important for all living organisms. Zinc functions not only as a nutritional factor, but also as a second messenger. However, the effects of intracellular zinc on the B cell-receptor (BCR) signaling pathway are not poorly understood. Here, we indicate that the ZIP9 induces increase in intracellular zinc level and plays an important role in the phosphorylation of Akt and Erk in response to BCR activation. In DT40 cells, the enhancement of Akt and Erk phosphorylation requires intracellular zinc. To clarify this event, we used chicken Zip9-knockout DT40 (cZip9KO) cells. The levels of Akt and Erk phosphorylation significantly decreased in cZip9KO cells treated with zinc pyrithione (ZnPy), and overexpressing the human Zip9 gene restored these biochemical events. Moreover, we found that the increase in intracellular zinc level depends on the expression of ZIP9. Additionally, intracellular zinc was localized at the Golgi, even if it was treated with ZnPy in cZip9KO cells. We concluded that ZIP9 regulates cytosolic zinc level, resulting in the enhancement of Akt and Erk phosphorylation. Our observations provide new mechanistic insights into the BCR signaling pathway underlying the regulation of intracellular zinc level by ZIP9 in response to the BCR activation.