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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulation of CD40 function by its isoforms generated through alternative splicing
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Regulation of CD40 function by its isoforms generated through alternative splicing

机译：通过替代剪接产生的CD40亚型调节CD40功能

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摘要

CD40 is a member of the tumor necrosis factor receptor superfam- ily. The interaction between CD40 and CD40 ligand (CD154) acti- vates NF-KB, Jun N-terminal kinase. and Janus kinase/signal trans- ducers and activators of transcription pathways and promotes B cell growth, differentiation, and survival as well as IL-12 produc- tion in macrophages and dendritic cells. We demonstrate here the existence of multiple isoforms of CD40 mRNA generated by alter- native splicing and show that their expression is regulated differ- entially in activated macrophages and dendritic cells. Pre-CD40 RNA is spliced preferentially out to signal-transducible CD40 mRNA in the early stage of activation: half of the CD40 mRNA is replaced by the signal-nontransducible CD40 mRNAs in the later stages (24 h). Using IL-12 p40 gene expression as a reporter for CD40 signal- ing, we show that three of the alternative isoforms can disable signaling through CD40. The major alternative isoform lacks the membrane-associated endodomain and seems to reduce the amount of the signal-transducible form available on the cell sur- face. It would seem, therefore, that CD40 expression is controlled by posttranscriptional and posttranslational regulation through alternative splicing. Modulation of isoform expression may pro- vide a mechanism by which cells regulate their susceptibility to CD40L signaing.
机译：CD40是肿瘤坏死因子受体超家族的成员。 CD40和CD40配体（CD154）之间的相互作用激活了NF-KB，Jun N端激酶。以及Janus激酶/信号转导子和转录通路激活剂，促进巨噬细胞和树突状细胞中B细胞的生长，分化和存活以及IL-12的产生。我们在这里证明了通过可变剪接产生的CD40 mRNA的多种同工型，并表明它们的表达在活化的巨噬细胞和树突状细胞中受到不同的调节。前CD40 RNA在激活的早期被优先剪接到信号可转导的CD40 mRNA上：在后期（24 h）中，一半的CD40 mRNA被信号不可转导的CD40 mRNA取代。使用IL-12 p40基因表达作为CD40信号的报告基因，我们证明了三种备选同工型可以禁用通过CD40的信号。主要的替代同工型缺乏膜相关的内结构域，似乎减少了细胞表面可用的信号转导形式。因此，似乎CD40表达受转录和翻译后调控的替代剪接控制。异构体表达的调节可能提供了一种机制，通过该机制细胞可以调节其对CD40L信号的敏感性。

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