Department of Sciences, University of Basilicata, 85100 Potenza, Italy.
Int J Mol Sci. 2021 Mar 11;22(6):2858. doi: 10.3390/ijms22062858.
Pseudoxanthoma elasticum (PXE) is a complex autosomal recessive disease caused by mutations of ABCC6 transporter and characterized by ectopic mineralization of soft connective tissues. Compared to the other ABC transporters, very few studies are available to explain the structural components and working of a full ABCC6 transporter, which may provide some idea about its physiological role in humans. Some studies suggest that mutations of in the liver lead to a decrease in some circulating factor and indicate that PXE is a metabolic disease. It has been reported that ABCC6 mediates the efflux of ATP, which is hydrolyzed in PPi and AMP; in the extracellular milieu, PPi gives potent anti-mineralization effect, whereas AMP is hydrolyzed to Pi and adenosine which affects some cellular properties by modulating the purinergic pathway. Structural and functional studies have demonstrated that silencing or inhibition of ABCC6 with probenecid changed the expression of several genes and proteins such as and TNAP, as well as Lamin, and CDK1, which are involved in cell motility and cell cycle. Furthermore, a change in cytoskeleton rearrangement and decreased motility of HepG2 cells makes ABCC6 a potential target for anti-cancer therapy. Collectively, these findings suggested that ABCC6 transporter performs functions that modify both the external and internal compartments of the cells.
弹性假黄瘤（PXE）是一种由 ABCC6 转运蛋白基因突变引起的复杂常染色体隐性疾病，其特征是软结缔组织的异位矿化。与其他 ABC 转运蛋白相比，很少有研究能够解释完整 ABCC6 转运蛋白的结构组成和工作原理，这可能为其在人类中的生理作用提供一些思路。一些研究表明，肝脏中的突变导致一些循环因子的减少，并表明 PXE 是一种代谢疾病。据报道，ABCC6 介导 ATP 的外排，ATP 在 PPi 和 AMP 中水解；在细胞外环境中，PPi 具有很强的抗矿化作用，而 AMP 则水解为 Pi 和腺苷，通过调节嘌呤能途径影响一些细胞特性。结构和功能研究表明，用丙磺舒沉默或抑制 ABCC6 会改变几种基因和蛋白质的表达，如和 TNAP，以及 Lamin 和 CDK1，它们参与细胞运动和细胞周期。此外，细胞骨架重排的变化和 HepG2 细胞运动能力的降低使 ABCC6 成为抗癌治疗的潜在靶点。综上所述，这些发现表明 ABCC6 转运蛋白具有修饰细胞内外区室的功能。
