Regulation of the BAG3 chaperone network under mechanical stress

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The cochaperone BAG3 coordinates gene expression, protein translation and autophagy to maintain the proteome under mechanical stress. It orchestrates a multi-component chaperone complex, which recognizes mechanically unfolded and damaged forms of the actin-crosslinking protein filamin and initiates their autophagic degradation. In addition, BAG3 engages in Hippo signalling to stimulate filamin transcription as a compensatory response, and participates in the regulation of the mTOR kinase to balance protein translation and autophagic flux. In agreement with its central proteostasis function under mechanical stress, BAG3 impairment causes muscle weakness in patients and animal models and is required for the adhesion and migration of immune and tumour cells. However, little is known about the regulation of the BAG3 chaperone machinery under mechanical stress. Here we will elucidate how force- and exercise-induced alterations of the phosphorylation status of BAG3 affect mechanical stress protection. We will investigate the impact of these phosphorylation events on the composition and dynamic formation of BAG3 chaperone complexes and on BAG3-mediated autophagic degradation, gene expression and mTOR regulation. Because available data reveal an extensive dephosphorylation of BAG3 under mechanical stress, involved phosphatases will be identified and characterized. Our study will establish key regulatory events that enable mammalian cells to cope with mechanical stress.