GRP78 Interacting Partner Bag5 Responds to ER Stress and Protects Cardiomyocytes From ER Stress‐Induced Apoptosis

Abstract

Bag5 is a member of the BAG family of molecular chaperone regulators and is unusual in that it consists of five BAG domains, which function as modulators of chaperone activity. Bag family proteins play a key role in cellular as well as in cardiac function and their differential expression is reported in heart failure. In this study, we examined the importance of a Bag family member protein, Bag5, in cardiomyocytes during endoplasmic reticulum (ER) stress. We found that expression of Bag5 in cardiomyocytes is significantly increased with the induction of ER stress in a time dependent manner. We have taken gain-in and loss-of functional approaches to characterize Bag5 protein function in cardiomyocytes. Adenoviral mediated expression of Bag5 significantly decreased cell death as well as improved cellular viability in ER stress. Along with this, ER stress-induced CHOP protein expression is significantly decreased in cells that overexpress Bag5. Conversely, we found that siRNA-mediated knockdown of Bag5 caused cell death, increased cytotoxicity and decreased cellular viability in cardiomyocytes. Mechanistically, we found that Bag5 protein expression is significantly increased in the ER during ER stress and that this in turn modulates GRP78 protein stability and reduces ER stress. This study suggests that Bag5 is an important regulator of ER function and so could be exploited as a tool to improve cardiomyocyte function under stress conditions.

Fenofibrate improves high-fat diet-induced and palmitate-induced endoplasmic reticulum stress and inflammation in skeletal muscle

“…GRP78 and CHOP are two different markers of ER stress. Usually, activated GRP78, which inactivates the insulin-signaling pathway, acts as a chaperone protein to enhance the ER's protein-folding capacity and to reduce the unfolded protein load in the ER [24]. Meanwhile, CHOP reactivates protein synthesis and oxidation in the ER.…”

Evidence for the Role of BAG3 in Mitochondrial Quality Control in Cardiomyocytes

“…All experiments were performed under protocols approved by the Temple University Institutional Animal Care and Use Committee. Cardiomyocytes were isolated from 1 to 2 days old Sprague-Dawley rats (Charles River) as previously described (Gupta et al, 2016). Isolated cells were cultured in Dulbecco's modified Eagle medium (DMEM, Life Technologies, Carlsbad, CA) supplemented with 2% fetal bovine serum (FBS, Denville Scientific inc., Holliston, MA) and 25 mg/ml Gentamicin (Life Technologies).…”

Attenuation of intermittent hypoxia-induced apoptosis and fibrosis in pulmonary tissues via suppression of ER stress activation

“…At the early stage of ER stress, unfolded protein response (UPR) was activated to enhance ER chaperone protein production, such as glucose regulated protein-78 (Grp78). This molecular chaperone could restore ER function via facilitating protein folding [12]. If the activation of ER stress is prolonged, ER stressmediated apoptosis can be induced via three pathways, including protein kinase RNA (PKR)-like/Pancreatic ER kinase (PERK), activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1) pathways [13].…”