Hamilton B JoNell, Wang Xiao-Wei, Collins Jane, Bloch Donald, Bergeron Alan, Henry Brian, Terry Benjamin M, Zan Moe, Mouland Andrew J, Rigby William F C
Department of Medicine, Lebanon, New Hampshire 03756.
Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
J Biol Chem. 2008 Sep 12;283(37):25606-25616. doi: 10.1074/jbc.M802492200. Epub 2008 Jul 18.
We report a role for CA repeats in the 3'-untranslated region (3'-UTR) in regulating CD154 expression. Human CD154 is encoded by an unstable mRNA; this instability is conferred in cis by a portion of its 3'-UTR that includes a polypyrimidine-rich region and CA dinucleotide repeat. We demonstrate similar instability activity with the murine CD154 3'-UTR. This instability element mapped solely to a conserved 100-base CU-rich region alone, which we call a CU-rich response element. Surprisingly, the CA dinucleotide-rich region also regulated reporter expression but at the level of translation. This activity was associated with poly(A) tail shortening and regulated by heterogeneous nuclear ribonucleoprotein L levels. We conclude that the CD154 3'-UTR contains dual cis-acting elements, one of which defines a novel function for exonic CA dinucleotide repeats. These findings suggest a mechanism for the association of 3'-UTR CA-rich response element polymorphisms with CD154 overexpression and the subsequent risk of autoimmune disease.
我们报道了3'-非翻译区（3'-UTR）中的CA重复序列在调节CD154表达中的作用。人CD154由不稳定的mRNA编码；这种不稳定性由其3'-UTR的一部分顺式赋予，该部分包括富含多嘧啶的区域和CA二核苷酸重复序列。我们证明小鼠CD154 3'-UTR具有类似的不稳定性活性。这种不稳定元件单独映射到一个保守的100个碱基的富含CU的区域，我们将其称为富含CU的反应元件。令人惊讶的是，富含CA二核苷酸的区域也在翻译水平上调节报告基因的表达。这种活性与聚腺苷酸（poly(A)）尾巴缩短有关，并受不均一核核糖核蛋白L水平的调节。我们得出结论，CD154 3'-UTR包含双重顺式作用元件，其中一个为外显子CA二核苷酸重复序列定义了一种新功能。这些发现提示了一种机制，即3'-UTR富含CA的反应元件多态性与CD154过表达以及随后的自身免疫性疾病风险相关。
