Bidirectional regulation of HDAC5 by mAKAPβ signalosomes in cardiac myocytes

J Mol Cell Cardiol. 2018 May;118:13-25. doi: 10.1016/j.yjmcc.2018.03.001. Epub 2018 Mar 6.

Abstract

Class IIa histone deacetylases (HDACs) are transcriptional repressors whose nuclear export in the cardiac myocyte is associated with the induction of pathological gene expression and cardiac remodeling. Class IIa HDACs are regulated by multiple, functionally opposing post-translational modifications, including phosphorylation by protein kinase D (PKD) that promotes nuclear export and phosphorylation by protein kinase A (PKA) that promotes nuclear import. We have previously shown that the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) orchestrates signaling in the cardiac myocyte required for pathological cardiac remodeling, including serving as a scaffold for both PKD and PKA. We now show that mAKAPβ is a scaffold for HDAC5 in cardiac myocytes, forming signalosomes containing HDAC5, PKD, and PKA. Inhibition of mAKAPβ expression attenuated the phosphorylation of HDAC5 by PKD and PKA in response to α- and β-adrenergic receptor stimulation, respectively. Importantly, disruption of mAKAPβ-HDAC5 anchoring prevented the induction of HDAC5 nuclear export by α-adrenergic receptor signaling and PKD phosphorylation. In addition, disruption of mAKAPβ-PKA anchoring prevented the inhibition by β-adrenergic receptor stimulation of α-adrenergic-induced HDAC5 nuclear export. Together, these data establish that mAKAPβ signalosomes serve to bidirectionally regulate the nuclear-cytoplasmic localization of class IIa HDACs. Thus, the mAKAPβ scaffold serves as a node in the myocyte regulatory network controlling both the repression and activation of pathological gene expression in health and disease, respectively.

Keywords: HDAC5; PKA; PKD; Phosphorylation; Scaffold; mAKAP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / chemistry
  • A Kinase Anchor Proteins / metabolism*
  • Active Transport, Cell Nucleus / drug effects
  • Adrenergic Agents / pharmacology
  • Animals
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • HEK293 Cells
  • Histone Deacetylases / metabolism*
  • Humans
  • Myocytes, Cardiac / metabolism*
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Domains
  • Rats
  • Signal Transduction

Substances

  • A Kinase Anchor Proteins
  • Adrenergic Agents
  • Akap6 protein, rat
  • Cyclic AMP-Dependent Protein Kinases
  • Hdac5 protein, rat
  • Histone Deacetylases