Decreased stability and translation of T cell receptor ζ mRNA with an alternatively spliced 3′-untranslated region contribute to ζ chain down-regulation in patients with systemic lupus erythematosus
Decreased stability and translation of T cell receptor ζ mRNA with an alternatively spliced 3′-untranslated region contribute to ζ chain down-regulation in patients with systemic lupus erythematosus
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DOI：
10.1074/jbc.m501048200
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发表时间：
2005-05-13
影响因子：
4.8
通讯作者：
Tsokos, GC
中科院分区：
文献类型：
--
作者：
Chowdhury, B;Tsokos, CG;Tsokos, GC
系统性红斑狼疮患者 T 细胞受体 (TCR) zeta 链异常表达的分子机制尚不清楚。之前我们证明，虽然正常T细胞表达高水平的具有野生型（WT）3'非翻译区（3'UTR）的TCR zeta mRNA，但系统性红斑狼疮T细胞表现出显着高水平的具有选择性剪接（AS）3'UTR形式的TCR zeta mRNA，该形式是通过剪接删除TCR zeta转录物的核苷酸672-1233而衍生的。在此我们报告，与具有 WT 3' UTR 的 TCR zeta mRNA 相比，具有 AS 3' UTR 的 TCR zeta mRNA 的稳定性较低。 AS 3' UTR（而非 WT 3' UTR）赋予荧光素酶基因类似的不稳定性。对转染的 COS-7 细胞的细胞裂解物进行免疫印迹表明，具有 AS 3' UTR 的 TCR zeta 产生少量的 16-kDa 蛋白。体外转录和翻译也从具有 AS 3' UTR 的 TCR zeta 产生少量蛋白质。总而言之，我们的研究结果表明，TCR zeta 3' UTR 的 672-1233 bp 核苷酸对其稳定性起着关键作用，并且还具有人类 T 细胞中 TCR zeta 链表达翻译调节所需的元件。
The molecular mechanisms involved in the aberrant expression of T cell receptor (TCR) zeta chain of patients with systemic lupus erythematosus are not known. Previously we demonstrated that although normal T cells express high levels of TCR zeta mRNA with wild-type (WT) 3' untranslated region (3' UTR), systemic lupus erythematosus T cells display significantly high levels of TCR zeta mRNA with the alternatively spliced (AS) 3' UTR form, which is derived by splice deletion of nucleotides 672-1233 of the TCR zeta transcript. Here we report that the stability of TCR zeta mRNA with an AS 3' UTR is low compared with TCR zeta mRNA with WT 3' UTR. AS 3' UTR, but not WT 3' UTR, conferred similar instability to the luciferase gene. Immunoblotting of cell lysates derived from transfected COS-7 cells demonstrated that TCR zeta with AS 3' UTR produced low amounts of 16-kDa protein. In vitro transcription and translation also produced low amounts of protein from TCR zeta with AS 3' UTR. Taken together our findings suggest that nucleotides 672-1233 bp of TCR zeta 3' UTR play a critical role in its stability and also have elements required for the translational regulation of TCR zeta chain expression in human T cells.