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Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4

Johannes Backs1, Barbara C Worst, Lorenz H Lehmann

  • 1Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany. johannes.backs@med.uni-heidelberg.de

The Journal of Cell Biology
|November 2, 2011
PubMed

Insights

Protein kinase A (PKA) counters cardiac hypertrophy by cleaving Histone deacetylase 4 (HDAC4), generating a fragment that inhibits myocyte enhancer factor 2 (MEF2) activity and opposes calcium/calmodulin-dependent protein kinase II (CaMKII) signaling.

Area of Science:

  • Molecular biology
  • Cardiovascular research
  • Cell signaling

Background:

  • Histone deacetylase 4 (HDAC4) is a key regulator of gene expression, notably repressing myocyte enhancer factor 2 (MEF2) and serum response factor (SRF).
  • Calcium/calmodulin-dependent protein kinase II (CaMKII) signaling in cardiomyocytes promotes hypertrophy and pathological remodeling, partly via HDAC4 phosphorylation and subsequent MEF2 activation.

Purpose of the Study:

  • To elucidate a novel mechanism by which protein kinase A (PKA) antagonizes CaMKII-driven prohypertrophic signaling in cardiomyocytes.
  • To investigate the role of HDAC4 proteolysis in mediating the opposing effects of PKA and CaMKII pathways.

Main Methods:

  • Investigated the interaction between PKA, CaMKII, and HDAC4 in cardiomyocyte signaling.
  • Analyzed the generation and function of an N-terminal HDAC4 cleavage product (HDAC4-NT).
  • Assessed the impact of HDAC4-NT on MEF2 and SRF transcription factor activity and cardiomyocyte hypertrophy.

Main Results:

  • PKA signaling induces regulated proteolysis of HDAC4, generating an N-terminal fragment (HDAC4-NT).
  • HDAC4-NT selectively inhibits MEF2 activity, thereby counteracting the prohypertrophic effects of CaMKII.
  • This PKA-mediated mechanism antagonizes CaMKII's prohypertrophic actions without compromising cardiomyocyte survival.

Conclusions:

  • HDAC4 acts as a molecular nexus integrating antagonistic PKA and CaMKII signaling pathways in cardiomyocytes.
  • Regulated proteolysis of HDAC4 by PKA offers a novel mechanism for controlling MEF2 activity and preventing pathological cardiac remodeling.
  • These findings provide insights into the molecular basis of cardioprotection and cellular processes involving opposing kinase signaling.

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