Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, Israel.
Hum Mol Genet. 2013 Apr 1;22(7):1316-27. doi: 10.1093/hmg/dds535. Epub 2012 Dec 18.
Inability to properly degrade unfolded or misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and unfolded protein response. This is particularly important in cases of diseases in which the mutant proteins undergo ER-associated degradation (ERAD), as in Gaucher disease (GD). GD is a genetic, autosomal recessive disease that results from mutations in the GBA1 gene, encoding the lysosomal enzyme acid β-glucocerebrosidase (GCase). We have shown that mutant GCase variants undergo ERAD, the degree of which is a major determinant of disease severity. Most ERAD substrates undergo polyubiquitination and proteasomal degradation. Therefore, one expects that mutant GCase variants are substrates for several E3 ubiquitin ligases in different cells. We tested the possibility that ITCH, a known E3 ubiquitin ligase, with a pivotal role in proliferation and differentiation of the skin, recognizes mutant GCase variants and mediates their polyubiquitination and degradation. Our results strongly suggest that ITCH interacts with mutant GCase variants and mediates their lysine 48 polyubiquitination and degradation.
内质网（ER）中未折叠或错误折叠蛋白质的正确降解能力下降会导致内质网应激和未折叠蛋白反应。在某些情况下，突变蛋白经历 ER 相关降解（ERAD），例如戈谢病（GD），这一点尤为重要。GD 是一种遗传性常染色体隐性疾病，由编码溶酶体酶酸性β-葡糖苷脑苷脂酶（GCase）的 GBA1 基因突变引起。我们已经表明，突变 GCase 变体经历 ERAD，其程度是疾病严重程度的主要决定因素。大多数 ERAD 底物经历多聚泛素化和蛋白酶体降解。因此，可以预期突变 GCase 变体是不同细胞中几种 E3 泛素连接酶的底物。我们测试了已知在皮肤增殖和分化中起关键作用的 E3 泛素连接酶 ITCH 是否识别突变 GCase 变体并介导其多泛素化和降解的可能性。我们的结果强烈表明 ITCH 与突变 GCase 变体相互作用，并介导其赖氨酸 48 多泛素化和降解。
