Receptor-independent protein kinase C alpha (PKCalpha) signaling by calpain-generated free catalytic domains induces HDAC5 nuclear export and regulates cardiac transcription

J Biol Chem. 2011 Jul 29;286(30):26943-51. doi: 10.1074/jbc.M111.234757. Epub 2011 Jun 3.


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 PKCα in ischemic myocardium activates PKC signaling in a receptor-independent manner by releasing a persistent and constitutively active free catalytic fragment, PKCα-CT. This unregulated kinase provokes cardiomyopathy, but the mechanisms remain unclear. Here, we demonstrate that PKCα-CT is a potent regulator of pathological cardiac gene expression. PKCα-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, PKCα-CT directly drives HDAC cytosolic relocalization. Activation of MEF2-dependent inflammatory pathway genes by PKCα-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Apoptosis / physiology
  • Calcium / metabolism
  • Calpain / genetics
  • Calpain / metabolism*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Gene Expression Regulation / physiology
  • HEK293 Cells
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mice
  • Mice, Transgenic
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myocardium / metabolism*
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism*
  • Protein Structure, Tertiary
  • Signal Transduction / physiology*
  • Transcription, Genetic / physiology*


  • Isoenzymes
  • Muscle Proteins
  • Protein Kinase C-alpha
  • Calpain
  • Hdac5 protein, mouse
  • Histone Deacetylases
  • Calcium