Phosphorylation of NBR1 by GSK3 modulates protein aggregation.

[inclusion body myositis]

The autophagy receptor NBR 1 (neighbor of BRCA 1 gene 1 ) binds UB /ubiquitin and the autophagosome-conjugated MAP 1 LC 3 /LC 3 (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 GSK 3 (glycogen synthase kinase 3 ) activity is involved in several of these proteinopathies . Here we show that NBR 1 is a substrate of GSK 3 . NBR 1 phosphorylation by GSK 3 at Thr 586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation . Indeed , NBR 1 phosphorylation decreases protein aggregation induced by puromycin or by the DES /desmin N 342 D 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 Atg 7 knockout mice . The relevance of NBR 1 phosphorylation in human pathology was investigated . Analysis of muscle biopsies of sporadic inclusion body myositis (sIBM ) patients revealed a strong decrease of NBR 1 phosphorylation in muscles of sIBM patients that directly correlated with the severity of protein aggregation . We propose that phosphorylation of NBR 1 by GSK 3 modulates the formation of protein aggregates and that this regulation mechanism is defective in a human muscle proteinopathy .

Diseases
Validation

Diseases presenting "muscle biopsies" symptom

cadasil

inclusion body myositis

pyruvate dehydrogenase deficiency

zellweger syndrome

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