Fei Erkang, Jia Nali, Yan Ming, Ying Zheng, Sun Qiang, Wang Hongfeng, Zhang Tao, Ma Xiaochuan, Ding Husheng, Yao Xuebiao, Shi Yunyu, Wang Guanghui
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
Biochem Biophys Res Commun. 2006 Aug 25;347(2):406-12. doi: 10.1016/j.bbrc.2006.06.092. Epub 2006 Jun 23.
The mutations in the gene encoding copper-zinc superoxide dismutase (SOD1) cause approximately 20% cases of familial amyotrophic lateral sclerosis (FALS), characterized by selective loss of motor neurons. Mutant SOD1 forms inclusions in tissues from FALS patients. However, the precise mechanism of the accumulation of mutant SOD1 remains unclear. Here we show that human SOD1 is a substrate modified by SUMO-1. A conversion of lysine 75 to an arginine within a SUMO consensus sequence in SOD1 completely abolishes SOD1 sumoylation. We further show that SUMO-1 modification, on both wild-type and mutant SOD1, increases SOD1 steady state level and aggregation. Moreover, SUMO-1 co-localizes onto the aggregates formed by SOD1. These findings imply that SUMO-1 modification on lysine 75 may participate in regulating SOD1 stability and its aggregation process. Thus, our results suggest that sumoylation of SOD1 may be involved in the pathogenesis of FALS associated with mutant SOD1.
编码铜锌超氧化物歧化酶（SOD1）的基因突变导致约20%的家族性肌萎缩侧索硬化症（FALS）病例，其特征为运动神经元的选择性丧失。突变型SOD1在FALS患者的组织中形成包涵体。然而，突变型SOD1积累的确切机制仍不清楚。在此我们表明，人SOD1是一种被SUMO-1修饰的底物。SOD1中SUMO共有序列内的赖氨酸75向精氨酸的转变完全消除了SOD1的类泛素化修饰。我们进一步表明，SUMO-1修饰，无论是对野生型还是突变型SOD1，都会增加SOD1的稳态水平和聚集。此外，SUMO-1与SOD1形成的聚集体共定位。这些发现意味着赖氨酸75上的SUMO-1修饰可能参与调节SOD1的稳定性及其聚集过程。因此，我们的结果表明，SOD1的类泛素化修饰可能参与了与突变型SOD1相关的FALS的发病机制。
