Abstract 281: Differential Regulation of Histone Deacetylase 4 by CaM Kinase II and Protein Kinase A in Response to Cardiac Beta-Adrenergic Signaling
Beta-adrenergic receptor (beta-AR) signaling plays a pivotal role in the pathogenesis of cardiac hypertrophy and heart failure. Although numerous studies have investigated the mechanisms of beta-AR signal transduction, the final steps towards cardiac transcription are not well understood. Class II histone deacetylases (HDACs) are signal-responsive repressors of the MEF2 transcription factor, which drives pathological remodeling of the heart. Multiple kinases phosphorylate these HDACs, resulting in 14–3–3 chaperone-mediated nuclear export of HDACs and de-repression of MEF2 target genes. Whether beta-AR signaling modulates phosphorylation of class II HDACs has not been previously investigated. Here, we show that beta-AR signaling via CaMKII induces 14 –3–3 binding selectively to HDAC4 but not to other HDACs, and mutant mice lacking CaMKII delta and gamma fail to phosphorylate HDAC4 in response to beta-AR stimulation. Another beta-AR downstream kinase, protein kinase A (PKA), did not induce 14 –3–3 binding to HDAC4, but surprisingly generated an N-terminal cleavage product of HDAC4, which acts as a CaMKII-insensitive transcriptional repressor of MEF2. PKA-mediated cleavage of HDAC4 requires not only the cleavage site but also a distant PKA-responsive domain in the C-terminal half of HDAC4. We identified three serine residues in the C-terminal half of HDAC4 that are critical for PKA-induced cleavage. The serine protease inhibitor AEBSF inhibited HDAC4 cleavage and prevented repression of MEF2 activity in response to adenylyl cyclase activation. These findings identify HDAC4 as a target of PKA and CaMKII. Whereas CaMKII induces cytosolic accumulation of HDAC4 and de-represses its target genes, PKA generates an HDAC4 cleavage product that represses transcription. We propose that the balance and timing of PKA versus CaMKII activation determines the degree of HDAC4-dependent cardiac transcription. These findings have implications not only for understanding the molecular basis of pathological cardiac remodeling, but also for a variety of cellular processes in which CaMKII and PKA exert opposing effects.