Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Protein Homeostasis

Background:

• Defective protein quality control (PQC) is linked to various diseases.
• The co-chaperone BAG3 (BCL-2-associated athanogene 3) is vital for PQC, especially in cardiomyocytes under stress.
• BAG3 mutations, including E455K, are associated with heart failure and dilated cardiomyopathy (DCM).

Purpose of the Study:

• To investigate the role of BAG3 in the heart.
• To elucidate the mechanisms by which the BAG3 E455K mutation causes DCM.
• To understand the interaction between BAG3 and HSP70 in maintaining cardiac function.

Main Methods:

• Generated cardiac-specific Bag3 knockout (KO) and E455K-knockin mouse models.
• Analyzed cardiac phenotypes, protein interactions (BAG3-HSP70), and protein solubility.
• Assessed levels of small heat shock proteins (sHSPs) in cardiac tissue.

Main Results:

• Both Bag3-KO and E455K mice developed DCM, indicating the mutation causes loss of function.
• The E455K mutation disrupted the interaction between BAG3 and HSP70.
• Mutant mice showed reduced sHSP levels and accumulation of insoluble proteins essential for cardiomyocyte function.

Conclusions:

• The interaction between BAG3 and HSP70 is essential for stabilizing sHSPs and maintaining cardiac protein homeostasis.
• BAG3 dysfunction contributes to heart failure through impaired protein quality control.
• Enhancing BAG3 levels may offer a therapeutic strategy for heart failure.