TNF receptor-associated factor 6 interacts with ALS-linked misfolded superoxide dismutase 1 and promotes aggregation.

Autor:	Semmler S; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec H3A 2B4, Canada.; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada., Gagné M; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada.; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Quebec H3T 1J4, Canada., Garg P; Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada., Pickles SR; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada.; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Quebec H3T 1J4, Canada., Baudouin C; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada.; Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium., Hamon-Keromen E; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada.; Université Pierre et Marie Curie, 75005 Paris, France., Destroismaisons L; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada., Khalfallah Y; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada.; Department of Neurosciences, Université de Montréal, Montréal, Quebec H3T 1J4, Canada., Chaineau M; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec H3A 2B4, Canada.; Montreal Neurological Institute, McGill University, Montréal, Quebec H3A 2B4, Canada., Caron E; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada., Bayne AN; Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec H3A 2B4, Canada., Trempe JF; Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec H3A 2B4, Canada., Cashman NR; Department of Medicine (Neurology), University of British Columbia and Vancouver Coastal Health Research Institute, Brain Research Centre, Vancouver, British Columbia V6T 2B5, Canada., Star AT; Human Health Therapeutics Portfolio, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada., Haqqani AS; Human Health Therapeutics Portfolio, National Research Council of Canada, Ottawa, Ontario, K1A 0R6, Canada., Durcan TM; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec H3A 2B4, Canada.; Montreal Neurological Institute, McGill University, Montréal, Quebec H3A 2B4, Canada., Meiering EM; Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada., Robertson J; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 0S8, Canada., Grandvaux N; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada.; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Quebec H3T 1J4, Canada., Plotkin SS; Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada., McBride HM; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec H3A 2B4, Canada.; Montreal Neurological Institute, McGill University, Montréal, Quebec H3A 2B4, Canada., Vande Velde C; Centre de Recherche du Centre Hospitalier de Université de Montréal, Montréal, Quebec H2X 0A9, Canada c.vande.velde@umontreal.ca.; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Quebec H3T 1J4, Canada.; Department of Neurosciences, Université de Montréal, Montréal, Quebec H3T 1J4, Canada.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2020 Mar 20; Vol. 295 (12), pp. 3808-3825. Date of Electronic Publication: 2020 Feb 06.
DOI:	10.1074/jbc.RA119.011215
Abstrakt:	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. (© 2020 Semmler et al.)
Databáze:	MEDLINE
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