Journal Article

Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation

Zheng Ying, Hongfeng Wang, Huadong Fan, Xiaodong Zhu, Jiawei Zhou, Erkang Fei and Guanghui Wang

in Human Molecular Genetics

Volume 18, issue 22, pages 4268-4281
Published in print November 2009 | ISSN: 0964-6906
Published online August 2009 | e-ISSN: 1460-2083 | DOI:
Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation

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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.

Journal Article.  7031 words.  Illustrated.

Subjects: Genetics and Genomics

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