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首页> 外文期刊>FEBS Open Bio >ZNT7 binds to CD40 and influences CD154‐triggered p38 MAPK activity in B lymphocytes—a possible regulatory mechanism for zinc in immune function
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ZNT7 binds to CD40 and influences CD154‐triggered p38 MAPK activity in B lymphocytes—a possible regulatory mechanism for zinc in immune function

机译：ZNT7与CD40结合并影响B淋巴细胞中CD154触发的p38 MAPK活性-锌在免疫功能中的可能调节机制

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Zinc deficiency impairs the immune system leading to frequent infections. Although zinc is known to play critical roles in maintaining healthy immune function, the underlying molecular targets are largely unknown. In this study, we demonstrate that zinc is important for the CD154–CD40‐mediated activation of downstream signaling pathways in human B lymphocytes. CD40 is a receptor localized on the cell surface of many immune cells, including B lymphocytes. It binds to CD154, a membrane protein expressed on antigen‐activated T helper (Th) lymphocytes. This CD154‐CD40 interaction leads to B‐cell activation. We showed that cellular zinc deficiency impaired the CD154‐CD40‐mediated p38 mitogen‐activated protein kinase (p38 MAPK) phosphorylation. We also showed that zinc supplemental treatment of B lymphocytes had limited effect on this CD40‐mediated p38 MAPK signaling. Most importantly, we demonstrated that the zinc transporter protein zinc transporter 7 (ZNT7) interacted with CD40 using immunoprecipitation analyses. ZNT7 knockdown in B lymphocytes had a negative effect on the cell surface expression of CD40. Consequently, the CD40‐mediated p38 MAPK signaling transduction was down‐regulated in ZNT7KD B lymphocytes. Conversely, this p38 MAPK signaling activity was up‐regulated by overexpression (OE) of ZNT7 in B lymphocytes. Moreover, we found that ZNT7 knockdown in B lymphocytes constitutively up‐ and down‐regulated the inhibitor of i kappa B kinase and AKT serine/threonine kinase phosphorylation, respectively, which implies the activation of survival signaling in ZNT7KD B cells. We conclude that CD40 is the target molecule for ZNT7 in regulation of immune function of B lymphocytes.
机译：缺锌会损害免疫系统，导致经常感染。尽管已知锌在维持健康的免疫功能中起着关键作用，但潜在的分子靶标很大程度上未知。在这项研究中，我们证明锌对于人类B淋巴细胞中CD154–CD40介导的下游信号通路的激活很重要。 CD40是位于许多免疫细胞（包括B淋巴细胞）细胞表面的受体。它与CD154结合，CD154是在抗原激活的T辅助（Th）淋巴细胞上表达的膜蛋白。这种CD154-CD40相互作用导致B细胞激活。我们发现细胞锌缺乏会损害CD154‐CD40介导的p38丝裂原活化蛋白激酶（p38 MAPK）的磷酸化。我们还显示锌补充治疗B淋巴细胞对此CD40介导的p38 MAPK信号传导的作用有限。最重要的是，我们证明了锌转运蛋白锌转运蛋白7（ZNT7）使用免疫沉淀分析与CD40相互作用。 B淋巴细胞中的ZNT7敲低对CD40的细胞表面表达有负面影响。因此，ZNT7KD B淋巴细胞中CD40介导的p38 MAPK信号转导被下调。相反，该p38 MAPK信号转导活性通过B淋巴细胞中ZNT7的过表达（OE）上调。此外，我们发现B淋巴细胞中的ZNT7敲低分别上调和下调了i kappa B激酶和AKT丝氨酸/苏氨酸激酶磷酸化的抑制剂，这暗示着ZNT7KD B细胞中生存信号的激活。我们得出结论，CD40是ZNT7调控B淋巴细胞免疫功能的靶分子。

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