Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5

Abstract

A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation-and CRM1-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression.Coordinated changes in gene transcription during cell growth and differentiation require mechanisms for coupling intracellular signaling pathways with the genome. The acetylation of nucleosomal histones has emerged as a central mechanism in the control of gene transcription during such cellular transitions (20). Acetylation of histones by histone acetyltransferases promotes transcription by relaxing chromatin structure, whereas histone deacetylation by histone deacetylases (HDACs) reverses this process, resulting in transcriptional repression. How these chromatin-modifying enzymes are linked to, and controlled by, intracellular signaling is only beginning to be understood.There are two classes of HDACs that can be distinguished by their structures and expression patterns. Class I HDACs (HDAC1, HDAC2, and HDAC3) are expressed ubiquitously and are composed mainly of a catalytic domain (13). In contrast, class II HDACs (HDAC4, HDAC5, HDAC7, and HDAC9) display more restricted expression patterns and contain an N-terminal extension, which mediates interactions with other transcriptional cofactors and confers responsiveness to calcium-dependent signaling (12,25,33). Signaling by calcium/ calmodulin-dependent protein kinase (CaMK) results in phosphorylation of the N termini of class II HDACs, which govern their intracellular localization and interactions with other factors (29, 32). Phosphorylation of signal-responsive serine residues creates docking sites for the 14-3-3 family of chaperone proteins, which promote shuttling of HDACs from the nucleus to the cytoplasm in a CRM1-dependent fashion (14,21,30,31,48).CaMK signaling to class II HDACs governs the activity of th...

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

“…Interestingly, both HDAC5 and HDAC7 undergo active nucleocytoplasmic shuttling in response to extracellular signals (McKinsey et al, 2000;Vega et al, 2004), which may allow for fine-tuning of angiogenesis-related genes. In contrast, HDAC6 resides exclusively in the cytoplasm presumably due to its tetradecapeptide repeat domain and its association with cytoskeletal components (Bertos et al, 2004;Valenzuela-Fernández et al, 2008).…”

Class IIa histone deacetylases: regulating the regulators

“…All class IIa members are detectable in mouse heart suggesting a functional role for the MEF2 class IIa HDACs axis in cardiac hypertrophy (Zhang et al, 2002a). Indeed, expression of constitutively repressive mutants of HDAC4, -5 and -9 prevents hypertrophic gene expression in primary rat cardiomyocytes (Zhang et al, 2002a;Vega et al, 2004a;. In contrast, disruption of HDAC9 leads to hyperactivation of MEF2-dependent transcriptional activity in response to pathologic cardiac hypertrophic signals (Zhang et al, 2002a).…”

CRM1 mediates nuclear export of HDAC7 independently of HDAC7 phosphorylation and association with 14‐3‐3s

“…In addition to CaMKs, protein kinase D family kinases and Mirk/dyrk1B also play a role in subcellular distribution of class IIa HDACs [21][22][23][24][25]. Nonetheless, it is not clear whether phosphorylation of these conserved residues is essential for nuclear export of HDAC7.…”