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

Xi Fang1, Julius Bogomolovas1,2, Tongbin Wu1

  • 1Department of Medicine, UCSD, La Jolla, California, USA.

The Journal of Clinical Investigation
|July 25, 2017
PubMed

Insights

Defects in the BAG3 protein, crucial for heart cell protein quality control, lead to dilated cardiomyopathy (DCM). The E455K mutation impairs BAG3

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.

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