Résumé :
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Autophagy is essential for cell homeostasis through degradation of proteins and organelles by lysosomes, thus maintaining a balance between synthesis, degradation and recycling. Excessive protein clearance in disused muscles, cancer or some myopathies like vacuolar myopathy leads to muscle atrophy whereas protein aggregation has been suggested to be toxic in neurodegenerative diseases like Alzheimer's disease and some myopathies like IBM (Inclusion Body Myositis). PI3K-AKT pathway regulates both protein synthesis and degradation by activating translation initiation and inhibiting the FoxO transcription factor which controls the induction of the autophagy pathway.In a yeast two-hybrid screen, we identified an interaction between the serine threonine kinase GSK3 (Glycogen Synthase Kinase 3), an AKT downstream target, and the autophagic receptor NBR1 (Neighbor of BRCA1 gene 1) and confirmed it by co-affinity purification. NBR1 binds ubiquitinated proteins and targets them to autophagy degradation through interaction with p62 and LC3. It also acts as a scaffold protein in Fibroblast Growth Factor Receptor signalling pathways and in Serum Response Factor-dependent muscle gene expression and protein turnover in disused muscles. Expression of a dominant negative form of GSK3B in myotubes caused a profound hypertrophy and dysregulation of GSK3 has been involved in the formation of protein aggregates in Huntington and Alzheimer's disease. The interaction between NBR1 and GSK3 suggests a novel mechanism of autophagy regulation by the PI3K-AKT pathway. In the context of muscle atrophy, we may ask whether GSK3 activity regulates ubiquitinated protein aggregation together with NBR1 and if this regulation contributes to GSK3 roles on muscle size and pathological protein aggregations. We have shown that NBR1 is a substrate of GSK3. Phosphorylation of NBR1 by GSK3 stabilises NBR1 and prevents the formation of ubiquitinated proteins aggregates en route to autophagy degradation. GSK3 might thus regulate NBR1 shuttle between signalling and autophagy complexes and synchronize both NBR1 functions. In order to test this hypothesis, study of GSK3 potential regulation of NBR1 localisation and interaction partners in a model of autophagy induction in disused muscles is under investigation. The study of the regulation of this process will provide valuable information for autophagy-related myopathies and for other pathologies, including cancer and neurodegenerative diseases.
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