title: Phosphorylation of NBR1 by GSK3 modulates protein aggregation.
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.
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule (LBMC) CNRS UMR5239; Ecole Normale Supérieure de Lyon; Lyon, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Nicot
authors.affiliation: Venetian Institute of Molecular Medicine and Department of Biomedical Science; University of Padova; Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lo Verso
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule (LBMC) CNRS UMR5239; Ecole Normale Supérieure de Lyon; Lyon, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ratti
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule (LBMC) CNRS UMR5239; Ecole Normale Supérieure de Lyon; Lyon, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Pilot-Storck
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule (LBMC) CNRS UMR5239; Ecole Normale Supérieure de Lyon; Lyon, France; Service de Neuropathologie; Groupement Hospitalier Est; Hospices Civils de Lyon; Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Streichenberger
authors.affiliation: Venetian Institute of Molecular Medicine and Department of Biomedical Science; University of Padova; Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule (LBMC) CNRS UMR5239; Ecole Normale Supérieure de Lyon; Lyon, France; Centre de Biotechnologies Cellulaires; Groupement Hospitalier Est; Hospices Civils de Lyon; Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule (LBMC) CNRS UMR5239; Ecole Normale Supérieure de Lyon; Lyon, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Goillot
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D000071193:Autophagy-Related Protein 7; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D018979:Myositis, Inclusion Body / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D066329:Protein Aggregates / Q000502:physiology*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054875:Ubiquitination
chemical_list: C502661:Atg7 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; C549756:NBR1 protein, human; C486326:Nbr1 protein, mouse; D066329:Protein Aggregates; D011506:Proteins; D038362:Glycogen Synthase Kinase 3; D000071193:Autophagy-Related Protein 7
keywords: GSK3; NBR1; autophagy; sIBM; skeletal muscle; sporadic inclusion body myositis; ubiquitinated protein aggregates