HnRNP L and L-like cooperate in multiple-exon regulation of CD45 alternative splicing.
HnRNP L and L-like cooperate in multiple-exon regulation of CD45 alternative splicing.
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DOI：
10.1093/nar/gks221
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发表时间：
2012-07
影响因子：
14.9
通讯作者：
Bindereif A
中科院分区：
文献类型：
--
作者：
Preussner M;Schreiner S;Hung LH;Porstner M;Jäck HM;Benes V;Rätsch G;Bindereif A
CD 45编码在免疫系统的多种细胞中表达的跨膜蛋白酪氨酸磷酸酶。通过组合使用三个可变外显子4-6，产生在其胞外结构域不同的同种型，从而调节磷酸酶活性和免疫应答。这些CD 45外显子的选择性剪接涉及两种异质性核糖核蛋白，hnRNP L及其细胞类型特异性paradhnRNP L样（LL）。为了解决外显子4-6的复杂组合剪接，我们研究了人B细胞中与CD 45剪接模式相关的hnRNP L/LL蛋白表达，应用RNA-Seq。此外，在HeLa细胞中进行突变和RNA结合分析。我们的结论是，hnRNP LL的功能作为主要的CD 45剪接阻遏物，与两个CA元件在外显子6作为其主要目标。在外显子4中，一个元件被hnRNP L和LL两者靶向。相比之下，外显子5本身从未被抑制，仅与外显子4和6共同调节。稳定的L/LL相互作用需要CD 45 RNA，特别是外显子4和6。我们提出了一种新的组合选择性剪接模型：HnRNP L和LL在CD 45前体mRNA上合作，桥接外显子4和6并环出外显子5，从而实现对三个可变外显子的完全抑制。
CD45 encodes a trans-membrane protein-tyrosine phosphatase expressed in diverse cells of the immune system. By combinatorial use of three variable exons 4–6, isoforms are generated that differ in their extracellular domain, thereby modulating phosphatase activity and immune response. Alternative splicing of these CD45 exons involves two heterogeneous ribonucleoproteins, hnRNP L and its cell-type specific paralog hnRNP L-like (LL). To address the complex combinatorial splicing of exons 4–6, we investigated hnRNP L/LL protein expression in human B-cells in relation to CD45 splicing patterns, applying RNA-Seq. In addition, mutational and RNA-binding analyses were carried out in HeLa cells. We conclude that hnRNP LL functions as the major CD45 splicing repressor, with two CA elements in exon 6 as its primary target. In exon 4, one element is targeted by both hnRNP L and LL. In contrast, exon 5 was never repressed on its own and only co-regulated with exons 4 and 6. Stable L/LL interaction requires CD45 RNA, specifically exons 4 and 6. We propose a novel model of combinatorial alternative splicing: HnRNP L and LL cooperate on the CD45 pre-mRNA, bridging exons 4 and 6 and looping out exon 5, thereby achieving full repression of the three variable exons.
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影响因子：
64.5
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通讯作者：
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