Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl
Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl
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DOI：
10.1073/pnas.1014376107
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Zhuang, Zhengping
中科院分区：
文献类型：
--
作者：
Lu, Jie;Chiang, Jeffrey;Zhuang, Zhengping
戈谢病（GD）是人类最常见的溶酶体贮积症，由编码葡萄糖脑苷脂酶（GCase）的基因突变引起。三种类型的GD患者的临床表现各不相同，即使在具有相同突变的患者中也存在表型异质性。为了深入了解GD中发生表型异质性的原因，我们研究了来自三种类型GD患者的培养皮肤成纤维细胞中GCase催化活性净丧失的机制。结果表明，GCase的催化活性的损失与其数量减少有关，而不是突变酶功能能力的降低。使用蛋白酶体抑制剂lactacystin导致GCase表达增加，表明GD中蛋白质降解的机制。此外，GCase与TCP 1环复合物（TRiC）（正确蛋白质折叠的调节剂）的结合减少，可能导致GD细胞中新生GCase的成熟缺陷。此外，GCase和c-Cbl（一种E3泛素连接酶）之间增加的相互作用可能参与GD中GCase的降解和丢失。研究结果表明，参与GCase成熟和降解的特定分子介质可能是相同基因型患者表型变异的原因，并且这些介质可以在治疗上靶向增加GD患者的GCase活性。
Gaucher disease (GD), the most common lysosomal storage disorder of humans, is caused by mutations in the gene coding for the enzyme glucocerebrosidase (GCase). Clinical manifestations vary among patients with the three types of GD, and phenotypic heterogeneity occurs even among patients with identical mutations. To gain insight into why phenotypic heterogeneity occurs in GD, we investigated mechanisms underlying the net loss of GCase catalytic activity in cultured skin fibroblasts derived from patients with the three types of GD. The findings indicate that the loss of catalytic activity of GCase correlates with its quantitative reduction, rather than a decrease in functional capacity of mutant enzyme. Use of a proteasome inhibitor, lactacystin, resulted in increased expression of GCase, suggesting a mechanism of protein degradation in GD. Furthermore, reduced binding of GCase to TCP1 ring complex (TRiC), a regulator of correct protein folding, may result in defective maturation of nascent GCase in GD cells. Additionally, increased interaction between GCase and c-Cbl, an E3 ubiquitin ligase, may be involved in the degradation and loss of GCase in GD. The findings suggest that specific molecular mediators involved in GCase maturation and degradation could be responsible for phenotypic variation among patients with the same genotypes and that these mediators could be therapeutically targeted to increase GCase activity in patients with GD.