Regulation of CD154 Expression

CD154过度表达是类风湿性关节炎(RA)和系统性红斑狼疮(SLE)的标志。这种关键免疫分子过度表达的病因尚不清楚。其次，以抗体·为基础的方法靶向CD154受到毒性的限制。这两个问题强调了更好地了解CD154生物合成调控的必要性。我们已经确定了多嘧啶束结合蛋白(PTS)通过与3‘UTRCU·富元件(CURE)结合，在介导CD154 mRNA周转中的作用。这些研究揭示了一种新的翻译调控途径，即通过在CD154 3‘UTR中发现的一个多态CA重复序列来调节CD154 mRNA的聚腺苷酸化。我们将这种由CA二核苷酸重复组成的新的顺式作用元件称为富CA·元件(CARE)。重要的是，CD153‘非编码区CA重复序列是多态的，某些等位基因与CD154的过度表达以及RA和SLE的发生有关。

CD154 overexpression is a hallmark of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). The etiology of the overexpression of this critical immune molecule is not understood. Second, the targeting of CD154 by antibody·based approaches is limited by toxicity. These two issues underscore the need for better understanding of the regulation of CD154 biosynthesis. We have established the role of polypyrimidine tract binding (PTS) proteins in mediating CD154 mRNA turnover through binding to a 3'UTR CU·rich element (CURE). These studies uncovered a novel pathway of translational regulation through a polymorphic CA repeat found in the CD154 3'UTR which regulates CD154 mRNA polyadenylation. We refer to this novel cis·acting element, consisting of CA dinucleotide repeats, as the CA·rich element (CARE). Importantly, the CD153'UTR CA repeats are polymorphic with certain alleles associated with CD154 overexpression and the development of RA and SLE.