Regulation of the BAG3 chaperone network under mechanical stress

辅伴侣蛋白BAG3协调基因表达、蛋白质翻译和自噬以在机械应力下维持蛋白质组。它协调多组分伴侣复合物，其识别肌动蛋白交联蛋白细丝蛋白的机械展开和损坏形式，并启动其自噬降解。此外，BAG3参与Hippo信号传导以刺激细丝蛋白转录作为补偿反应，并参与mTOR激酶的调节以平衡蛋白质翻译和自噬通量。与其在机械应力下的中心蛋白质稳态功能一致，BAG3损伤导致患者和动物模型的肌无力，并且是免疫和肿瘤细胞粘附和迁移所必需的。然而，鲜为人知的是，机械应力下的BAG3分子伴侣机制的调节。在这里，我们将阐明力和运动诱导的BAG3磷酸化状态的改变如何影响机械应力保护。我们将研究这些磷酸化事件对BAG3分子伴侣复合物的组成和动态形成以及对BAG3介导的自噬降解、基因表达和mTOR调控的影响。由于现有数据揭示了机械应力下BAG3的广泛去磷酸化，因此将鉴定和表征所涉及的磷酸酶。我们的研究将建立使哺乳动物细胞能够科普机械应力的关键调控事件。

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.