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Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development

Significance Zinc deficiency is known to trigger lymphopenia, but the mechanisms behind zinc-mediated lymphocyte maintenance have been unclear. We demonstrated that zinc uptake into cells through the zinc transporter ZIP10 is essential for cell survival in early B-cell development. The ablation of ZIP10 caused an increase in caspase activity accompanied by reduced intracellular zinc in the early B-cell developmental stages. The JAK-STAT pathways regulated ZIP10 expression, and ZIP10 expression was correlated with STAT activation in B-cell lymphoma samples. Our results establish a physiological role for ZIP10 in early B-cell survival. The immune system is influenced by the vital zinc (Zn) status, and Zn deficiency triggers lymphopenia; however, the mechanisms underlying Zn-mediated lymphocyte maintenance remain elusive. Here we investigated ZIP10, a Zn transporter expressed in the early B-cell developmental process. Genetic ablation of Zip10 in early B-cell stages resulted in significant reductions in B-cell populations, and the inducible deletion of Zip10 in pro-B cells increased the caspase activity in parallel with a decrease in intracellular Zn levels. Similarly, the depletion of intracellular Zn by a chemical chelator resulted in spontaneous caspase activation leading to cell death. Collectively, these findings indicated that ZIP10-mediated Zn homeostasis is essential for early B-cell survival. Moreover, we found that ZIP10 expression was regulated by JAK-STAT pathways, and its expression was correlated with STAT activation in human B-cell lymphoma, indicating that the JAK-STAT-ZIP10-Zn signaling axis influences the B-cell homeostasis. Our results establish a role of ZIP10 in cell survival during early B-cell development, and underscore the importance of Zn homeostasis in immune system maintenance.