Transgenic Expression of MicroRNA-185 Causes a Developmental Arrest of T Cells by Targeting Multiple Genes Including Mzb1
Transgenic Expression of MicroRNA-185 Causes a Developmental Arrest of T Cells by Targeting Multiple Genes Including Mzb1
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DOI：
10.1074/jbc.m113.503532
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发表时间：
2013-10-18
影响因子：
4.8
通讯作者：
van Oers, Nicolai S. C.
中科院分区：
文献类型：
--
作者：
Belkaya, Serkan;Murray, Sean E.;van Oers, Nicolai S. C.
MiR-185是一种针对B细胞中Bruton酪氨酸激酶的microRNA(MiR)，miR-185的减少与B细胞自身抗体的产生有关。在海马神经元中，miR-185针对肌浆/内质网钙ATPase 2和一种新的高尔基体抑制剂。在患有染色体22q11.2缺失综合征的90-95%的患者中，这种miR单倍体不足，这些患者可能会出现免疫、心脏和甲状旁腺问题，学习障碍，以及成人精神分裂症的高发。神经元中miR-185水平的降低导致突触前神经递质的释放。许多22q11.2缺失综合征患者的胸腺发育不良，导致外周T细胞淋巴细胞减少和异常的T辅助细胞倾斜。MiR-185在胸腺细胞中的分子靶点尚不清楚。使用miR-185 T细胞转基因方法，在T细胞受体(TCR)选择检查点和阳性选择期间，增加miR-185水平会抑制T细胞的发育。这导致了外周T细胞淋巴细胞减少。Mzb1、NFATc3和Camk4被鉴定为miR-185的新靶点。MiR-185的升高增加了依赖TCR的细胞内钙水平，而miR-185的敲除则减弱了这些钙反应。这些影响与内质网钙调节因子Mzb1的减少是一致的。在一些22q11.2缺失综合征患者的胸腺细胞提取液中，Mzb1水平升高，这与他们的miR-185单倍体缺陷一致。我们的发现表明，miR-185通过靶向包括Mzb1在内的几个mRNAs来调节T细胞的发育。
miR-185 is a microRNA (miR) that targets Bruton's tyrosine kinase in B cells, with reductions in miR-185 linked to B cell autoantibody production. In hippocampal neurons, miR-185 targets both sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and a novel Golgi inhibitor. This miR is haploinsufficient in 90-95% of individuals with chromosome 22q11.2 deletion syndrome, patients who can present with immune, cardiac, and parathyroid problems, learning disorders, and a high incidence of schizophrenia in adults. The reduced levels of miR-185 in neurons cause presynaptic neurotransmitter release. Many of the 22q11.2 deletion syndrome patients have a thymic hypoplasia, which results in a peripheral T cell lymphopenia and unusual T helper cell skewing. The molecular targets of miR-185 in thymocytes are unknown. Using an miR-185 T cell transgenic approach, increasing levels of miR-185 attenuated T cell development at the T cell receptor (TCR) selection checkpoint and during positive selection. This caused a peripheral T cell lymphopenia. Mzb1, Nfatc3, and Camk4 were identified as novel miR-185 targets. Elevations in miR-185 enhanced TCR-dependent intracellular calcium levels, whereas a knockdown of miR-185 diminished these calcium responses. These effects concur with reductions in Mzb1, an endoplasmic reticulum calcium regulator. Consistent with their haploinsufficiency of miR-185, Mzb1 levels were elevated in thymocyte extracts from several 22q11.2 deletion syndrome patients. Our findings indicate that miR-185 regulates T cell development through its targeting of several mRNAs including Mzb1.