Receptor-independent Protein Kinase Cα (PKCα) Signaling by Calpain-generated Free Catalytic Domains Induces HDAC5 Nuclear Export and Regulates Cardiac Transcription

Receptor-mediated activation of protein kinase (PK) C is a central pathway regulating cell growth, homeostasis, and programmed death. Recently, we showed that calpain-mediated proteolytic processing of PKC alpha in ischemic myocardium activates PKC signaling in a receptor-independent manner by releasing a persistent and constitutively active free catalytic fragment, PKC alpha-CT. This unregulated kinase provokes cardiomyopathy, but the mechanisms remain unclear. Here, we demonstrate that PKC alpha-CT is a potent regulator of pathological cardiac gene expression. PKC alpha-CT constitutively localizes to nuclei and directly promotes nucleo-cytoplasmic shuttling of HDAC5, inducing expression of apoptosis and other deleterious genes. Whereas PKD activation is required for HDAC5 nuclear export induced by unprocessed PKCs activated by phorbol ester, PKC alpha-CT directly drives HDAC cytosolic relocalization. Activation of MEF2-dependent inflammatory pathway genes by PKC alpha-CT can induce a cell-autonomous transcriptional response that mimics, but anticipates, actual inflammation. Because calpain-mediated processing of PKC isoforms occurs in many tissues wherein calcium is increased by stress or injury, our observation that the catalytically active product of this interaction is a constitutively active transcriptional regulator has broad ramifications for understanding and preventing the pathological transcriptional stress response.