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

Yan Zhang, Scot J. Matkovich, Xiujun Duan, Abhinav Diwan, Min Young Kang, Gerald W. Dorn

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)26943-26951
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number30
DOIs
StatePublished - Jul 29 2011

Fingerprint Dive into the research topics of 'Receptor-independent protein kinase Cα (PKCα) signaling by calpain-generated free catalytic domains induces HDAC5 nuclear export and regulates cardiac transcription'. Together they form a unique fingerprint.

  • Cite this