Back to Search
Start Over
Phosphorylation of NBR1 by GSK3 modulates protein aggregation.
- Source :
-
Autophagy [Autophagy] 2014 Jun; Vol. 10 (6), pp. 1036-53. - Publication Year :
- 2014
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8635
- Volume :
- 10
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Autophagy
- Publication Type :
- Academic Journal
- Accession number :
- 24879152
- Full Text :
- https://doi.org/10.4161/auto.28479