Biological significance of the expression of a Wilson disease mutant protein

我们研究了肝豆状核变性蛋白ATP7B的细胞内定位。虽然我们描述了ATP7B的晚期内体定位，但其他人已经报道了不同的结果。在本研究中，我们利用不同的细胞系和晚期内体特异蛋白的表达载体(Int J Mol Med 11；293-298：2003，Am J Pathol 166；499-510：2005)证实了该蛋白存在于晚期内体中。以前我们报道过表达一种威尔逊病突变蛋白(ATP7B H1069Q)可以诱导细胞内形成类似Mallory小体的包涵体。我们证明了蛋白酶体功能的抑制诱导了类似的包涵体，包涵体的形成影响了高尔基体的结构。因此，包涵体的形成可能会影响高尔基体的功能(Exp Cell RES 288；6069：2003，Cell Motil Cytoskel 57；37-52：2004)。此外，去除抑制剂后，蛋白酶体抑制所诱导的包涵体反向消失。这一过程与自噬降解有关(Exp Cell RES 288；60-69：2003)。此外，包涵体的形成影响胞浆蛋白的分布，并可能影响这些蛋白的功能(Exp Cell Res In Press)。

We have examined the intracellular localization of Wilson disease protein ATP7B. While we described the late endosomal localization of ATP7B, others have been reported the different results. In the present study we confirmed that this protein resides in the late endosomes using various cell lines and expression vectors for the late endosome specific proteins (Int J Mol Med 11;293-298:2003, Am J Pathol 166;499-510:2005).Previously we reported that expression of a Wilson disease mutant protein (ATP7B H1069Q) induced formation of intracellular inclusion bodies similar to Mallory body. We demonstrated inhibition of proteasome function induced similar inclusion bodies and the formation of the inclusion body affected the architecture of the Golgi apparatus. Therefore, formation of the inclusion body may affect the function of the Golgi apparatus (Exp Cell Res 288;6069:2003, Cell Motil Cytoskel 57;37-52:2004). Furthermore, the inclusion body induced by proteasome inhibition reversely disappeared after the removal of the inhibitor. This process was associated with the autophagic degradation (Exp Cell Res 288;60-69:2003). Furthermore, the formation of the inclusion body affected the distribution of cytosolic proteins and might affect the function of these proteins (Exp Cell Res in press).