Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development
Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development
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DOI：
10.1073/pnas.1323549111
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发表时间：
2014-08-12
影响因子：
11.1
通讯作者：
Fukada, Toshiyuki
中科院分区：
文献类型：
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作者：
Miyai, Tomohiro;Hojyo, Shintaro;Fukada, Toshiyuki
免疫系统受到重要锌（Zn）状态的影响，锌缺乏会引发淋巴细胞减少症;然而，锌介导的淋巴细胞维持的机制仍然难以捉摸。在这里，我们研究ZIP 10，锌转运蛋白在早期B细胞发育过程中表达。在早期B细胞阶段Zip 10的基因消融导致B细胞群体的显著减少，并且在前B细胞中Zip 10的诱导性缺失增加了与细胞内Zn水平降低平行的半胱天冬酶活性。类似地，通过化学螯合剂消耗细胞内Zn导致自发的半胱天冬酶激活，从而导致细胞死亡。总的来说，这些发现表明ZIP 10介导的锌稳态对于早期B细胞存活是必不可少的。此外，我们发现ZIP 10的表达受JAK-STAT通路的调节，并且其表达与人B细胞淋巴瘤中STAT的激活相关，表明JAK-STAT-ZIP 10-Zn信号轴影响B细胞稳态。我们的研究结果确立了ZIP 10在早期B细胞发育过程中细胞存活中的作用，并强调了锌稳态在免疫系统维持中的重要性。
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.