Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Cambridge CB2 0XY, UK.
Department of Chemistry, Biochemistry I, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany.
Cell Rep. 2018 Jul 3;24(1):27-37.e4. doi: 10.1016/j.celrep.2018.06.016.
Multiple sulfatase deficiency (MSD) is a fatal, inherited lysosomal storage disorder characterized by reduced activities of all sulfatases in patients. Sulfatases require a unique post-translational modification of an active-site cysteine to formylglycine that is catalyzed by the formylglycine-generating enzyme (FGE). FGE mutations that affect intracellular protein stability determine residual enzyme activity and disease severity in MSD patients. Here, we show that protein disulfide isomerase (PDI) plays a pivotal role in the recognition and quality control of MSD-causing FGE variants. Overexpression of PDI reduces the residual activity of unstable FGE variants, whereas inhibition of PDI function rescues the residual activity of sulfatases in MSD fibroblasts. Mass spectrometric analysis of a PDI+FGE variant covalent complex allowed determination of the molecular signature for FGE recognition by PDI. Our findings highlight the role of PDI as a disease modifier in MSD, which may also be relevant for other ER-associated protein folding pathologies.
多种硫酸酯酶缺乏症（MSD）是一种致命的遗传性溶酶体贮积病，其特征在于患者中所有硫酸酯酶的活性降低。硫酸酯酶需要在活性位点半胱氨酸上进行独特的翻译后修饰，形成甲酰甘氨酸，这一过程由甲酰甘氨酸生成酶（FGE）催化。影响细胞内蛋白质稳定性的 FGE 突变决定了 MSD 患者的残余酶活性和疾病严重程度。在这里，我们表明蛋白质二硫键异构酶（PDI）在识别和质量控制导致 MSD 的 FGE 变体中起着关键作用。PDI 的过表达降低了不稳定 FGE 变体的残余活性，而 PDI 功能的抑制则挽救了 MSD 成纤维细胞中硫酸酯酶的残余活性。PDI+FGE 变体共价复合物的质谱分析允许确定 PDI 识别 FGE 的分子特征。我们的发现强调了 PDI 在 MSD 中作为疾病修饰因子的作用，这对于其他 ER 相关蛋白质折叠病理学也可能相关。
