1. Regulation of ALS-Associated SOD1 Mutant SUMOylation and Aggregation by SENP and PIAS Family Proteins
- Author
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Dan Suzuki, Takako Niikura, and Harmony Wada
- Subjects
0301 basic medicine ,SENP1 ,Mutant ,SOD1 ,Lysine ,SUMO protein ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Superoxide Dismutase-1 ,0302 clinical medicine ,Animals ,Humans ,Protein inhibitor of activated STAT ,chemistry.chemical_classification ,biology ,Chemistry ,Amyotrophic Lateral Sclerosis ,Sumoylation ,nutritional and metabolic diseases ,General Medicine ,Protein Inhibitors of Activated STAT ,nervous system diseases ,Cell biology ,Ubiquitin ligase ,Cysteine Endopeptidases ,HEK293 Cells ,030104 developmental biology ,Enzyme ,Mutation ,biology.protein ,Protein Multimerization ,030217 neurology & neurosurgery - Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease specific to motor neurons. Pathogenic mutations in an ALS-associated gene encoding superoxide dismutase 1 (SOD1) have been identified in familial ALS (fALS) cases. SOD1 with fALS-linked mutations is prone to form cytotoxic aggregates that cause cellular dysfunction. We previously demonstrated that the modification of SOD1 by small ubiquitin-like modifier (SUMO) 3 enhances the aggregation of fALS-linked SOD1 mutants. SUMOylation is a reversible post-translational modification targeting lysine residues. SUMO conjugation is mediated by the enzymes E1, E2, and E3, and deconjugation is catalyzed by deSUMOylation enzymes. To understand the process of SOD1 aggregation, we examined the involvement of protein inhibitor of activated STAT (PIAS) family and sentrin-specific protease (SENP) family proteins in the SUMOylation of SOD1 mutants. We found that all four types of PIAS family proteins, E3 ligase of SUMOylation, increased SUMOylation of SOD1 mutants. Among three SENP family proteins tested, deSUMOylation enzymes, SENP1, exhibited the most efficient deconjugation effect. In co-expression experiments, PIASy and SENP1 increased and decreased the number of cells exhibiting SOD1-mutant aggregation, respectively, confirming the effect of these enzymes on SOD1 aggregation. These findings suggest that regulation of SUMOylation affects the pathogenesis of ALS.
- Published
- 2020