Human Molecular Genetics Advance Access originally published online on August 6, 2009
Human Molecular Genetics 2009 18(22):4268-4281; doi:10.1093/hmg/ddp380
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation
1 Laboratory of Molecular Neuropathology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science & Technology of China, Hefei, Anhui 230027, People's Republic of China and 2 Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China
* To whom correspondence should be addressed. Tel: +86 5513607058; Fax: +86 5513607058; Email: wghui{at}ustc.edu.cn
Received June 23, 2009; Accepted August 4, 2009
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.