Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation
Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation
复制标题
Gp78 是一种与 ER 相关的 E3，可促进 SOD1 和 ataxin-3 降解
DOI：
10.1093/hmg/ddp380
复制
发表时间：
2009-11-15
影响因子：
3.5
通讯作者：
Wang, Guanghui
中科院分区：
文献类型：
--
作者：
Ying, Zheng;Wang, Hongfeng;Wang, Guanghui
超氧化物歧化酶-1(SOD1)和ataxin-3是与家族性肌萎缩侧索硬化症和Machado-Joseph病/脊髓小脑型共济失调3型相关的两种神经退行性疾病蛋白。正常和突变类型的SOD1和ataxin-3都被蛋白酶体降解。最近研究发现，这两种蛋白与内质网(ER)有关。哺乳动物gp78是一种参与ER相关降解的E3泛素连接酶(ERAD)。在这里，我们证明了gp78与SOD1和ataxin-3都相互作用。Gp78的过表达促进了这两种蛋白的泛素化和降解，而gp78的敲除则稳定了这两种蛋白。此外，gp78还能抑制突变型SOD1的聚集形成，保护细胞免受突变型SOD1诱导的细胞死亡。此外，在转导这两种突变蛋白的细胞和ALS小鼠中，gp78的表达也增加。因此，我们的结果表明gp78在SOD1和ataxin-3的调节中发挥作用，以ERAD为靶点。
Superoxide dismutase-1 (SOD1) and ataxin-3 are two neurodegenerative disease proteins in association with familial amyotrophic lateral sclerosis and Machado-Joseph disease/spinocerebellar ataxia type 3. Both normal and mutant types of SOD1 and ataxin-3 are degraded by the proteasome. It was recently reported that these two proteins are associated with the endoplasmic reticulum (ER). Mammalian gp78 is an E3 ubiquitin ligase involved in ER-associated degradation (ERAD). Here, we show that gp78 interacts with both SOD1 and ataxin-3. Overexpression of gp78 promotes the ubiquitination and degradation of these two proteins, whereas knockdown of gp78 stabilizes them. Moreover, gp78 represses aggregate formation of mutant SOD1 and protect cells against mutant SOD1-induced cell death. Furthermore, gp78 is increased in cells transfected with these two mutant proteins as well as in ALS mice. Thus, our results suggest that gp78 functions in the regulation of SOD1 and ataxin-3 to target them for ERAD.