Regulation of ALS-Associated SOD1 Mutant SUMOylation and Aggregation by SENP and PIAS Family Proteins
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Regulation of ALS-Associated SOD1 Mutant SUMOylation and Aggregation by SENP and PIAS Family Proteins Harmony Wada 1 & Dan Suzuki 1 & Takako Niikura 1 Received: 15 December 2019 / Accepted: 19 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease specific to motor neurons. Pathogenic mutations in an ALSassociated gene encoding superoxide dismutase 1 (SOD1) have been identified in familial ALS (fALS) cases. SOD1 with fALSlinked 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. Keywords ALS . Aggregation . SUMO . SOD1
Introduction SUMOylation is a post-translational modification targeting lysine residues by small ubiquitin-like modifier (SUMO). SUMOylation induces changes in a variety of properties of target proteins, such as intracellular localization, activity, and stability, thus regulating cellular processes (Henley et al. 2014). The SUMO paralogs SUMO1-3 are distributed ubiquitously. SUMO2 and SUMO3, which differ by only three Nterminal residues, are referred to collectively as SUMO2/3. SUMO conjugation is mediated by the enzymes E1 (activating enzyme), E2 (conjugase), and E3 (ligase) (Wilkinson and Henley 2010). Protein inhibitor of activated STAT (PIAS) family proteins play roles in regulating STAT family signaling molecules and also promote SUMO modification as RINGtype SUMO ligase (Rytinki et al. 2009). Humans harbor four
* Takako Niikura [email protected] 1
Department of Information and Communication Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-ku, Tokyo 102-8554, Japan
ubiquitously expressed PIAS genes, PIAS1, PIASx, PIAS3, and PIASy. SUMOylation can be reversed by deSUMOylation enzymes, which deconjugate SUMO from target proteins. The sentrin-specific protease (SENP) family is one of three classes of SUMO-specific isopeptidases and proteases (Nayak
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