Bag5 Plays A Critical Role In The Regulation Of Cellular Homeostasis Through Fine- tuning Of Cellular Protein Quality Control

Background: Cardiac hypertrophy is one of the heart's adaptive responses, which may play a compensatory role in enhancing cardiac function during stress conditions. However, prolonged hypertrophy condition can lead to the progression of cardiac dysfunction and heart failure. Cellular chaperones and co-chaperones play a critical role in maintaining cellular homeostasis by regulating cellular protein quality control. A Bcl2 binding protein BAG5 acts as a co-chaperone to heat shock protein 70 and is known to be upregulated during oxidative stress. A recent study suggests that mutation of the BAG5 gene induces cardiac dysfunction by promoting dilated cardiomyopathy and arrhythmia. However, its role in cardiac hypertrophy is not clear. Method and Results: This study explores the BAG5 function through a protein-protein interaction study by immunoprecipitation and mass spectroscopy. Further, the role of BAG5 in cellular protein quality control and cardiac hypertrophy was tested using cardiomyocytes. Our protein interaction study suggests that BAG5 interacts with several cellular proteins involved in the biological process like Golgi-associated vesicular transport, fatty acid degradation, endoplasmic reticulum-assisted protein folding, chaperone-mediated protein degradation, and deubiquitinating process. Further, we found that knockdown of BAG5 causes induction of cellular hypertrophy, and overexpression of BAG5 reduces PE and ISO-induced cellular hypertrophy. Additionally, we found that BAG5 maintains a balance of cellular protein quality control, and knockdown of BAG5 causes upregulation of cellular autophagy Conclusion: BAG5 plays a critical role in maintaining cellular homeostasis and is protective during cardiac hypertrophy. Additionally, the reduction of BAG5 protein can promote maladaptive autophagy.