Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells
Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells
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DOI：
10.4049/jimmunol.1103142
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发表时间：
2012-06-01
影响因子：
4.4
通讯作者：
Moeroey, Tarik
中科院分区：
文献类型：
--
作者：
Gaudreau, Marie-Claude;Heyd, Florian;Moeroey, Tarik
通过选择性剪接调节前体mRNA的转录后修饰对于细胞功能、发育和免疫是重要的。受体酪氨酸磷酸酶CD 45在所有造血细胞上表达，已知其在T细胞的发育和活化中的作用。已知CD 45是可变剪接的，这是一个部分受异质核核糖核蛋白（hnRNP）L调控的过程。为了进一步研究hnRNP L的作用，我们已经产生了条件性hnRNP L敲除小鼠，并发现LckCre介导的hnRNP L缺失导致由双阴性4和双阳性细胞之间的过渡阶段的部分阻断引起的胸腺细胞结构减少。此外，hnRNP L-/-胸腺细胞表达异常水平的CD 45 RA剪接亚型，并显示高水平的磷酸化Lck在激活酪氨酸Y394，但缺乏磷酸化的抑制酪氨酸Y505。这表明基础Lck活性增加，并与hnRNP L-/-小鼠中双阴性4细胞的较高增殖率相关。hnRNP L的缺失还阻断了响应于鞘氨醇-1-磷酸和趋化因子CCL 21和CXCL 12的单阳性胸腺细胞向外周淋巴器官的迁移和外出，这很可能是由于编码GT3调节剂和影响细胞骨架组织的蛋白质的基因的异常剪接。我们的研究结果表明，hnRNP L调节T细胞的分化和迁移，通过调节前TCR和趋化因子受体信号。免疫学杂志，2012，188：5377-5388。
The regulation of posttranscriptional modifications of pre-mRNA by alternative splicing is important for cellular function, development, and immunity. The receptor tyrosine phosphatase CD45, which is expressed on all hematopoietic cells, is known for its role in the development and activation of T cells. CD45 is known to be alternatively spliced, a process that is partially regulated by heterogeneous nuclear ribonucleoprotein (hnRNP) L. To investigate the role of hnRNP L further, we have generated conditional hnRNP L knockout mice and found that LckCre-mediated deletion of hnRNP L results in a decreased thymic cellularity caused by a partial block at the transition stage between double-negative 4 and double-positive cells. In addition, hnRNP L-/- thymocytes express aberrant levels of the CD45RA splice isoforms and show high levels of phosphorylated Lck at the activator tyrosine Y394, but lack phosphorylation of the inhibitory tyrosine Y505. This indicated an increased basal Lck activity and correlated with higher proliferation rates of double-negative 4 cells in hnRNP L-/- mice. Deletion of hnRNP L also blocked the migration and egress of single-positive thymocytes to peripheral lymphoid organs in response to sphingosine-l-phosphate and the chemokines CCL21 and CXCL12 very likely as a result of aberrant splicing of genes encoding GTPase regulators and proteins affecting cytoskeletal organization. Our results indicate that hnRNP L regulates T cell differentiation and migration by regulating pre-TCR and chemokine receptor signaling. The Journal of Immunology, 2012, 188: 5377-5388.