Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4

Johannes Backs, Barbara C. Worst, Lorenz H. Lehmann, David M. Patrick, Zegeye Jebessa, Michael M. Kreusser, Qiang Sun, Lan Chen, Claudia Heft, Hugo A. Katus, Eric N. Olson

Research output: Contribution to journalArticle

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Abstract

Histone deacetylase 4 (HDAC4) regulates numerous gene expression programs through its signaldependent repression of myocyte enhancer factor 2 (MEF2) and serum response factor (SRF) transcription factors. In cardiomyocytes, calcium/calmodulin-dependent protein kinase II (CaMKII) signaling promotes hypertrophy and pathological remodeling, at least in part by phosphorylating HDAC4, with consequent stimulation of MEF2 activity. In this paper, we describe a novel mechanism whereby protein kinase A (PKA) overcomes CaMKIImediated activation of MEF2 by regulated proteolysis of HDAC4. PKA induces the generation of an N-terminal HDAC4 cleavage product (HDAC4-NT). HDAC4-NT selectively inhibits activity of MEF2 but not SRF, thereby antagonizing the prohypertrophic actions of CaMKII signaling without affecting cardiomyocyte survival. Thus, HDAC4 functions as a molecular nexus for the antagonistic actions of the CaMKII and PKA pathways. These findings have implications for understanding the molecular basis of cardioprotection and other cellular processes in which CaMKII and PKA exert opposing effects.

Original languageEnglish (US)
Pages (from-to)403-415
Number of pages13
JournalJournal of Cell Biology
Volume195
Issue number3
DOIs
StatePublished - Oct 31 2011

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MEF2 Transcription Factors
Histone Deacetylases
Cyclic AMP-Dependent Protein Kinases
Proteolysis
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Serum Response Factor
Cardiac Myocytes
Calcium-Calmodulin-Dependent Protein Kinases
Hypertrophy
Transcription Factors
Gene Expression

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Backs, J., Worst, B. C., Lehmann, L. H., Patrick, D. M., Jebessa, Z., Kreusser, M. M., ... Olson, E. N. (2011). Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4. Journal of Cell Biology, 195(3), 403-415. https://doi.org/10.1083/jcb.201105063

Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4. / Backs, Johannes; Worst, Barbara C.; Lehmann, Lorenz H.; Patrick, David M.; Jebessa, Zegeye; Kreusser, Michael M.; Sun, Qiang; Chen, Lan; Heft, Claudia; Katus, Hugo A.; Olson, Eric N.

In: Journal of Cell Biology, Vol. 195, No. 3, 31.10.2011, p. 403-415.

Research output: Contribution to journalArticle

Backs, J, Worst, BC, Lehmann, LH, Patrick, DM, Jebessa, Z, Kreusser, MM, Sun, Q, Chen, L, Heft, C, Katus, HA & Olson, EN 2011, 'Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4', Journal of Cell Biology, vol. 195, no. 3, pp. 403-415. https://doi.org/10.1083/jcb.201105063
Backs J, Worst BC, Lehmann LH, Patrick DM, Jebessa Z, Kreusser MM et al. Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4. Journal of Cell Biology. 2011 Oct 31;195(3):403-415. https://doi.org/10.1083/jcb.201105063
Backs, Johannes ; Worst, Barbara C. ; Lehmann, Lorenz H. ; Patrick, David M. ; Jebessa, Zegeye ; Kreusser, Michael M. ; Sun, Qiang ; Chen, Lan ; Heft, Claudia ; Katus, Hugo A. ; Olson, Eric N. / Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4. In: Journal of Cell Biology. 2011 ; Vol. 195, No. 3. pp. 403-415.
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