TNF receptor–associated factor 6 interacts with ALS-linked misfolded superoxide dismutase 1 and promotes aggregation
Autor: | Alexandra T. Star, Heidi M. McBride, Thomas M. Durcan, Elizabeth M. Meiering, Myriam Gagné, Janice Robertson, Christine Vande Velde, Jean-François Trempe, Sabrina Semmler, Neil R. Cashman, Pranav Garg, Elise Caron, Andrew N. Bayne, Nathalie Grandvaux, Steven S. Plotkin, Laurie Destroismaisons, Yousra Khalfallah, Sarah Pickles, Charlotte Baudouin, Mathilde Chaineau, Arsalan S. Haqqani, Emeline Hamon-Keromen |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Protein Folding animal diseases SOD1 Mitochondrion Protein aggregation Biochemistry DNA-binding protein Antibodies Cell Line Superoxide dismutase Protein Aggregates 03 medical and health sciences Superoxide Dismutase-1 Ubiquitin Animals RNA Small Interfering Molecular Biology TNF Receptor-Associated Factor 6 030102 biochemistry & molecular biology biology Chemistry Amyotrophic Lateral Sclerosis NF-kappa B Ubiquitination nutritional and metabolic diseases Molecular Bases of Disease Cell Biology Mitochondria Rats Cell biology Ubiquitin ligase nervous system diseases Disease Models Animal 030104 developmental biology TNF receptor associated factor nervous system Mutagenesis Site-Directed biology.protein RNA Interference Rats Transgenic |
Zdroj: | J Biol Chem |
Popis: | Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons leading to paralysis. Mutations in the gene encoding superoxide dismutase 1 (SOD1) are the second most common cause of familial ALS, and considerable evidence suggests that these mutations result in an increase in toxicity due to protein misfolding. We previously demonstrated in the SOD1(G93A) rat model that misfolded SOD1 exists as distinct conformers and forms deposits on mitochondrial subpopulations. Here, using SOD1(G93A) rats and conformation-restricted antibodies specific for misfolded SOD1 (B8H10 and AMF7-63), we identified the interactomes of the mitochondrial pools of misfolded SOD1. This strategy identified binding proteins that uniquely interacted with either AMF7-63 or B8H10-reactive SOD1 conformers as well as a high proportion of interactors common to both conformers. Of this latter set, we identified the E3 ubiquitin ligase TNF receptor–associated factor 6 (TRAF6) as a SOD1 interactor, and we determined that exposure of the SOD1 functional loops facilitates this interaction. Of note, this conformational change was not universally fulfilled by all SOD1 variants and differentiated TRAF6 interacting from TRAF6 noninteracting SOD1 variants. Functionally, TRAF6 stimulated polyubiquitination and aggregation of the interacting SOD1 variants. TRAF6 E3 ubiquitin ligase activity was required for the former but was dispensable for the latter, indicating that TRAF6-mediated polyubiquitination and aggregation of the SOD1 variants are independent events. We propose that the interaction between misfolded SOD1 and TRAF6 may be relevant to the etiology of ALS. |
Databáze: | OpenAIRE |
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