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Muscle A-kinase-anchoring protein-β-bound calcineurin toggles active and repressive transcriptional complexes of

Jinliang Li1, Shania Aponte Paris2, Hrishikesh Thakur1

  • 1From the Departments of Ophthalmology and Cardiovascular Medicine, Byers Eye Institute, and Spencer Center for Vision Research, Stanford Cardiovascular Institute, Stanford University, Palo Alto, California 94304-1209 and.

The Journal of Biological Chemistry
|December 8, 2018
PubMed

Insights

Muscle A-kinase-anchoring protein β (mAKAPβ) signalosomes regulate myocyte enhancer factor 2 D (MEF2D) activity. mAKAPβ promotes MEF2D dephosphorylation and acetylation, enhancing gene expression and muscle cell growth.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Muscle Development

Background:

  • Myocyte enhancer factor 2 (MEF2) transcription factors are crucial for skeletal and cardiac muscle development and function.
  • MEF2D activity is modulated by post-translational modifications, including dephosphorylation by calcineurin (CaN).
  • The scaffold protein muscle A-kinase-anchoring protein β (mAKAPβ) interacts with both MEF2D and CaN.

Purpose of the Study:

  • To investigate the role of mAKAPβ signalosomes in regulating MEF2D activity in C2C12 skeletal myoblasts.
  • To determine how mAKAPβ affects MEF2D post-translational modifications and transcriptional activity.
  • To elucidate the impact of mAKAPβ-mediated MEF2D regulation on myocyte differentiation and hypertrophy.

Main Methods:

  • Immunoprecipitation assays to assess protein interactions.
  • DNA-binding assays to evaluate MEF2D transcriptional activity.
  • Analysis of MEF2D phosphorylation, sumoylation, and acetylation states.
  • Assessment of histone deacetylase and acetyltransferase binding to MEF2D.

Main Results:

  • mAKAPβ signalosome formation is essential for CaN-mediated MEF2D dephosphorylation, desumoylation, and acetylation in C2C12 cells.
  • Reduced MEF2D phosphorylation correlated with a shift from histone deacetylase IIa to p300 histone acetyltransferase binding.
  • These modifications led to increased MEF2D-dependent gene expression and promoted ventricular myocyte hypertrophy.

Conclusions:

  • mAKAPβ signalosomes play a critical role in controlling MEF2D activity in striated muscle.
  • mAKAPβ acts as a nodal regulator within the myocyte intracellular signaling network, influencing muscle development and phenotype.
  • Targeting mAKAPβ signalosomes offers a potential strategy for modulating muscle cell growth and function.
Keywords:
A-kinase–anchoring proteinHDAC5MEF2Dcalcineuringene regulationhistone deacetylasemAKAPβmyoblastphosphatasephosphorylationscaffold proteinsignal transductionsignalosomeskeletal muscletranscription factor

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