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Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation
- Source :
- Human Molecular Genetics. 18:4268-4281
- Publication Year :
- 2009
- Publisher :
- Oxford University Press (OUP), 2009.
-
Abstract
- 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.
- Subjects :
- medicine.medical_specialty
Ubiquitin-Protein Ligases
SOD1
Mutant
Mice, Transgenic
Nerve Tissue Proteins
Biology
Endoplasmic-reticulum-associated protein degradation
Endoplasmic Reticulum
Cell Line
Mice
Superoxide Dismutase-1
Ubiquitin
Internal medicine
Genetics
medicine
Animals
Humans
Receptors, Cytokine
Ataxin-3
Molecular Biology
Genetics (clinical)
Superoxide Dismutase
Endoplasmic reticulum
Ubiquitination
Nuclear Proteins
nutritional and metabolic diseases
Neurodegenerative Diseases
General Medicine
nervous system diseases
Ubiquitin ligase
Cell biology
Receptors, Autocrine Motility Factor
Repressor Proteins
Endocrinology
Proteasome
Ataxin
biology.protein
Protein Binding
Transcription Factors
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....819ec4f3d4456380ada8d54b3f47d6ad