Muscle A-kinase-anchoring protein-β-bound calcineurin toggles active and repressive transcriptional complexes of myocyte enhancer factor 2D

Myocyte enhancer factor 2 (MEF2) transcription factors are key regulators of the development and adult phenotype of diverse tissues, including skeletal and cardiac muscles. Controlled by multiple post-translational modifications, MEF2D is an effector for the Ca2+/calmodulin-dependent protein phosphatase calcineurin (CaN, PP2B, and PPP3). CaN-catalyzed dephosphorylation promotes the desumoylation and acetylation of MEF2D, increasing its transcriptional activity. Both MEF2D and CaN bind the scaffold protein muscle A-kinase-anchoring protein beta (mAKAP beta), which is localized to the nuclear envelope, such that C2C12 skeletal myoblast differentiation and neonatal rat ventricular myocyte hypertrophy are inhibited by mAKAP beta signalosome targeting. Using immunoprecipitation and DNA-binding assays, we now show that the formation of mAKAP beta signalosomes is required for MEF2D dephosphorylation, desumoylation, and acetylation in C2C12 cells. Reduced MEF2D phosphorylation was coupled to a switch from type IIa histone deacetylase to p300 histone acetylase binding that correlated with increased MEF2D-dependent gene expression and ventricular myocyte hypertrophy. Together, these results highlight the importance of mAKAP beta signalosomes for regulating MEF2D activity in striated muscle, affirming mAKAP beta as a nodal regulator in the myocyte intracellular signaling network.