CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy
Johannes Backs, … , Shurong Chang, Eric N. Olson
Johannes Backs, … , Shurong Chang, Eric N. Olson
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1853-1864. https://doi.org/10.1172/JCI27438.
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Research Article Cardiology

CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy

Abstract

Class IIa histone deacetylases (HDACs) regulate a variety of cellular processes, including cardiac growth, bone development, and specification of skeletal muscle fiber type. Multiple serine/threonine kinases control the subcellular localization of these HDACs by phosphorylation of common serine residues, but whether certain class IIa HDACs respond selectively to specific kinases has not been determined. Here we show that calcium/calmodulin-dependent kinase II (CaMKII) signals specifically to HDAC4 by binding to a unique docking site that is absent in other class IIa HDACs. Phosphorylation of HDAC4 by CaMKII promotes nuclear export and prevents nuclear import of HDAC4, with consequent derepression of HDAC target genes. In cardiomyocytes, CaMKII phosphorylation of HDAC4 results in hypertrophic growth, which can be blocked by a signal-resistant HDAC4 mutant. These findings reveal a central role for HDAC4 in CaMKII signaling pathways and have implications for the control of gene expression by calcium signaling in a variety of cell types.

Authors

Johannes Backs, Kunhua Song, Svetlana Bezprozvannaya, Shurong Chang, Eric N. Olson

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Figure 2

Regulation of CaMKII subcellular localization.

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Regulation of CaMKII subcellular localization. (A) COS cells were transf...
(A) COS cells were transfected with CaMKIIδB-WT, CaMKIIδB-T287D, and CaMKIIδB-T287D/S332A. In contrast to the WT kinase, CaMKIIδB-T287D localized predominantly to the cytosol. Substitution of S332 rendered CaMKIIδB-T287D constitutively active and nuclear. (B) COS cells were cotransfected with CaMKIIδB-T287D/S332A and HDAC4 or HDAC5. Note that only HDAC4 was exported in response to the double CaMKIIδB mutant and colocalized with the kinase. (C and D) COS cells were first transfected with the indicated CaMKIIδB mutants and 12 hours later with HDAC4. Twelve hours after transfection with HDAC4, cells were treated for another 4 hours either with 1 nM leptomycin B (lower panel) or the vehicle ethanol (upper panel). Note that with leptomycin B, HDAC4 only accumulates in the nucleus in the presence of CaMKIIδB-T287D/S332A, which is active and nuclear, but not in the presence of CaMKIIδB-T287D or CaMKIIδB-T287D/K328,329N, which are active and cytosolic. (A–C) Representative images. Magnification, ×40. (D) Quantitative analysis of experiment shown in C.