Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
Telethon Institute of Genetics and Medicine (TIGEM), Federico II University, 80078 Naples, Italy.
Nat Commun. 2014 Dec 19;5:5840. doi: 10.1038/ncomms6840.
Sulfatases are key enzymatic regulators of sulfate homeostasis with several biological functions including degradation of glycosaminoglycans (GAGs) and other macromolecules in lysosomes. In a severe lysosomal storage disorder, multiple sulfatase deficiency (MSD), global sulfatase activity is deficient due to mutations in the sulfatase-modifying factor 1 (SUMF1) gene, encoding the essential activator of all sulfatases. We identify a novel regulatory layer of sulfate metabolism mediated by a microRNA. miR-95 depletes SUMF1 protein levels and suppresses sulfatase activity, causing the disruption of proteoglycan catabolism and lysosomal function. This blocks autophagy-mediated degradation, causing cytoplasmic accumulation of autophagosomes and autophagic substrates. By targeting miR-95 in cells from MSD patients, we can effectively increase residual SUMF1 expression, allowing for reactivation of sulfatase activity and increased clearance of sulfated GAGs. The identification of this regulatory mechanism opens the opportunity for a unique therapeutic approach in MSD patients where the need for exogenous enzyme replacement is circumvented.
硫酸酯酶是硫酸酯代谢平衡的关键酶调节剂，具有多种生物学功能，包括溶酶体中糖胺聚糖 (GAG) 和其他大分子的降解。在严重的溶酶体贮积症——多种硫酸酯酶缺乏症 (MSD) 中，由于硫酸酯酶修饰因子 1 (SUMF1) 基因的突变，导致所有硫酸酯酶的必需激活剂缺失，导致全球硫酸酯酶活性缺乏。我们发现了一种由 microRNA 介导的新的硫酸酯代谢调控层。miR-95 耗尽 SUMF1 蛋白水平并抑制硫酸酯酶活性，导致蛋白聚糖分解代谢和溶酶体功能障碍。这阻止了自噬介导的降解，导致自噬体和自噬底物在细胞质中积累。通过针对 MSD 患者细胞中的 miR-95，我们可以有效地增加残留 SUMF1 的表达，从而重新激活硫酸酯酶活性并增加硫酸化 GAG 的清除。该调控机制的发现为 MSD 患者提供了一种独特的治疗方法，避免了外源性酶替代的需求。
