Regulation of CD154 Expression

CD154过表达是风湿性关节炎（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学尚不清楚。其次，通过基于抗体的方法靶向CD154受到毒性的限制。这两个问题强调需要更好地了解CD154生物合成的调节。我们已经确定了多聚嘧啶束结合（PTS）蛋白通过与3'UTR CU·rich元件（CURE）结合在介导CD 154 mRNA周转中的作用。这些研究揭示了一种新的翻译调控途径，通过在CD154 3'UTR中发现的多态性CA重复序列来调控CD154 mRNA的多聚腺苷酸化。我们将这种由CA二核苷酸重复序列组成的顺式作用元件称为富CA元件（CARE）。重要的是，CD153'UTR CA重复序列是多态性的，某些等位基因与CD154过表达和RA和SLE的发展有关。

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.