1. Phosphorylation of NBR1 by GSK3 modulates protein aggregation.
- Author
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Nicot AS, Lo Verso F, Ratti F, Pilot-Storck F, Streichenberger N, Sandri M, Schaeffer L, and Goillot E
- Subjects
- Animals, Autophagy physiology, Autophagy-Related Protein 7, Cell Line, Cells, Cultured, Female, HEK293 Cells, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Knockout, Microtubule-Associated Proteins deficiency, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins metabolism, Models, Biological, Myositis, Inclusion Body metabolism, Myositis, Inclusion Body pathology, Phosphorylation, Proteins chemistry, Proteins genetics, Proteostasis Deficiencies genetics, Proteostasis Deficiencies metabolism, Proteostasis Deficiencies pathology, Ubiquitination, Glycogen Synthase Kinase 3 metabolism, Protein Aggregates physiology, Proteins metabolism
- Abstract
The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation. Numerous neurodegenerative and neuromuscular diseases are associated with inappropriate aggregation of ubiquitinated proteins and GSK3 (glycogen synthase kinase 3) activity is involved in several of these proteinopathies. Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. Indeed, NBR1 phosphorylation decreases protein aggregation induced by puromycin or by the DES/desmin N342D mutant found in desminopathy patients and stabilizes ubiquitinated proteins. Importantly, decrease of protein aggregates is due to an inhibition of their formation and not to their autophagic degradation as confirmed by data on Atg7 knockout mice. The relevance of NBR1 phosphorylation in human pathology was investigated. Analysis of muscle biopsies of sporadic inclusion body myositis (sIBM) patients revealed a strong decrease of NBR1 phosphorylation in muscles of sIBM patients that directly correlated with the severity of protein aggregation. We propose that phosphorylation of NBR1 by GSK3 modulates the formation of protein aggregates and that this regulation mechanism is defective in a human muscle proteinopathy.
- Published
- 2014
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