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Updated: Jul 15, 2025

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An Unbiased Screen Identified the Hsp70-BAG3 Complex as a Regulator of Myosin-Binding Protein C3

Andrea D Thompson1, Marcus J Wagner2, Juliani Rodriguez1

  • 1Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.

JACC. Basic to Translational Science
|October 4, 2023
PubMed

Insights

Familial hypertrophic cardiomyopathy (HCM) is linked to MYBPC3 gene variants. Researchers found that heat shock protein 70 and BAG3 regulate MyBP-C protein levels, offering potential therapeutic targets for HCM.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Genetic Cardiology

Background:

  • Familial hypertrophic cardiomyopathy (HCM) is a primary genetic heart muscle disease.
  • MYBPC3 gene variants are responsible for ~50% of familial HCM cases.
  • Reduced levels of myosin-binding protein C (MyBP-C) are a hallmark of HCM caused by MYBPC3 variants.

Purpose of the Study:

  • To identify novel pathways regulating MyBP-C protein homeostasis.
  • To uncover potential therapeutic targets for HCM by understanding MyBP-C regulation.

Main Methods:

  • Screened 2,426 bioactive compounds to identify modulators of MyBP-C levels.
  • Utilized JG98, an allosteric modulator of heat shock protein 70 (HSP70).
  • Investigated the role of HSP70-BAG3 complex in MyBP-C protein stability through genetic manipulation of BAG3.

Main Results:

  • Identified JG98, which inhibits HSP70 interaction with BAG domain co-chaperones.
  • Demonstrated that JG98 treatment reduces MyBP-C protein levels.
  • Showed that genetic reduction of BAG3 mimics JG98 effects, decreasing MYBPC3 protein levels.

Conclusions:

  • The heat shock protein 70-BAG3 complex is a novel regulator of MyBP-C protein stability.
  • This finding provides a new understanding of MyBP-C homeostasis.
  • Identified a potential therapeutic avenue for HCM by targeting the HSP70-BAG3 pathway.

Keywords:
BAG3MYBPC3hypertrophic cardiomyopathymolecular chaperones

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