βAdrenergic stimulation induces histone deacetylase 5 (HDAC5) nuclear accumulation in cardiomyocytes by B55α-PP2A-mediated dephosphorylation

Kate L. Weeks, Antonella Ranieri, Agnieszka Karaś, Bianca C. Bernardo, Alexandra ASHCROFT, Chris Molenaar, Julie R. McMullen, Metin Avkiran*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)
133 Downloads (Pure)

Abstract

Background--Class IIa histone deacetylase (HDAC) isoforms such as HDAC5 are critical signal-responsive repressors of maladaptive cardiomyocyte hypertrophy, through nuclear interactions with transcription factors including myocyte enhancer factor-2. βAdrenoceptor (βAR) stimulation, a signal of fundamental importance in regulating cardiac function, has been proposed to induce both phosphorylation-independent nuclear export and phosphorylation-dependent nuclear accumulation of cardiomyocyte HDAC5. The relative importance of phosphorylation at Ser259/Ser498 versus Ser279 in HDAC5 regulation is also controversial. We aimed to determine the impact of βAR stimulation on the phosphorylation, localization, and function of cardiomyocyte HDAC5 and delineate underlying molecular mechanisms. Methods and Results--A novel 3-dimensional confocal microscopy method that objectively quantifies the whole-cell nuclear/ cytoplasmic distribution of green fluorescent protein tagged HDAC5 revealed the b-AR agonist isoproterenol to induce b1-ARmediated and protein kinase A-dependent HDAC5 nuclear accumulation in adult rat cardiomyocytes, which was accompanied by dephosphorylation at Ser259/279/498. Mutation of Ser259/Ser498 to Ala promoted HDAC5 nuclear accumulation and myocyte enhancer factor-2 inhibition, whereas Ser279 ablation had no such effect and did not block isoproterenol-induced nuclear accumulation. Inhibition of the Ser/Thr phosphatase PP2A blocked isoproterenol-induced HDAC5 dephosphorylation. Coimmunoprecipitation revealed a specific interaction of HDAC5 with the PP2A targeting subunit B55a, as well as catalytic and scaffolding subunits, which increased > 3-fold with isoproterenol. Knockdown of B55α in neonatal cardiomyocytes attenuated isoproterenol-induced HDAC5 dephosphorylation. Conclusions--b-AR stimulation induces HDAC5 nuclear accumulation in cardiomyocytes by a mechanism that is protein kinase A-dependent but requires B55α-PP2A-mediated dephosphorylation of Ser259/Ser498 rather than protein kinase A-mediated phosphorylation of Ser279.

Original languageEnglish
Article numbere004861
Pages (from-to)1-14
JournalJournal of the American Heart Association
Volume6
Issue number4
Early online date25 Mar 2017
DOIs
Publication statusPublished - 5 Apr 2017

Keywords

  • Adrenergic stimulation
  • B-adrenergic signaling
  • B55a
  • Confocal imaging
  • Histone deacetylase 5
  • Hypertrophy/remodeling
  • Microscopy
  • Phosphatase
  • Phosphorylation
  • PP2A
  • Three dimensional

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