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Delineation of a Novel Pathway That Regulates CD154 (CD40 Ligand) Expression

机译：新型调节CD154（CD40配体）表达的途径的描述

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The expression of CD154 (CD40 ligand) by activated T lymphocytes plays a central role in humoral and cellular immunity. The fundamental importance of this protein in mounting an immune response has made it an attractive target for immunomodulation. Several studies have demonstrated that CD154 expression is regulated at the level of mRNA turnover in a manner distinct from other cytokine genes. We have purified, sequenced, and characterized the two major proteins that bind the CD154 3′ untranslated region (3′UTR) as members of the polypyrimidine tract binding protein (PTB) family. One of these proteins is a previously unreported alternatively spliced PTB isoform, which we call PTB-T. These proteins interact with a polypyrimidine-rich region within the CD154 3′UTR that lacks any known cis-acting instability elements. The polypyrimidine-rich region of the CD154 3′UTR was both necessary and sufficient to mediate changes in reporter gene expression and mRNA accumulation, indicating the presence of a novel cis-acting instability element. The presence of a cis-acting instability element in the polypyrimidine-rich region was confirmed using a tetracycline-responsive reporter gene approach. The function of this cis-acting element appears to be dependent on the relative cytoplasmic levels of PTB and PTB-T. Cotransfection of vectors encoding PTB-T consistently decreased the CD154 3′UTR-dependent luciferase expression. In contrast, transfection of plasmids encoding PTB tended to increase CD154 3′UTR-dependent luciferase expression. Thus, the CD154 3′UTR contains a novel cis-acting element whose function is determined by the binding of PTB and PTB-T. These data identify a specific pathway that regulates CD154 expression that can potentially be selectively targeted for the treatment of autoimmune disease and allograft rejection.
机译：活化的T淋巴细胞表达CD154（CD40配体）在体液和细胞免疫中起着核心作用。该蛋白在引发免疫应答中的根本重要性使其成为免疫调节的有吸引力的靶标。几项研究表明，CD154表达以不同于其他细胞因子基因的方式在mRNA周转水平上受到调节。我们已经纯化，测序和表征了结合CD154 3'非翻译区（3'UTR）的两个主要蛋白质，作为多嘧啶束结合蛋白（PTB）家族的成员。这些蛋白质之一是以前未报道的可变剪接的PTB亚型，我们称为PTB-T。这些蛋白质与CD154 3'UTR中富含多嘧啶的区域相互作用，而该区域缺少任何已知的 cis 作用不稳定元件。 CD154 3'UTR的富含聚嘧啶的区域对于介导报告基因表达和mRNA积累的变化既必要又充分，表明存在新型的顺式作用不稳定性元件。使用四环素反应性报告基因方法证实了富含聚嘧啶的区域中存在顺式作用不稳定性元件。此顺式作用元件的功能似乎取决于PTB和PTB-T的相对细胞质水平。编码PTB-T的载体的共转染始终降低CD154 3'UTR依赖的荧光素酶表达。相反，转染编码PTB的质粒倾向于增加CD154 3'UTR依赖的荧光素酶表达。因此，CD154 3'UTR包含新型的顺式作用元件，其功能由PTB和PTB-T的结合决定。这些数据确定了调节CD154表达的特定途径，该途径可能被选择性靶向治疗自身免疫性疾病和同种异体移植排斥。

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