Acetylation of Heat Shock Protein 20 (Hsp20) Regulates Human Myometrial Activity

• Published in: The Journal of biological chemistry Vol. 286; no. 39; pp. 34346 - 34355
• Main Authors: Karolczak-Bayatti, Magdalena, Sweeney, Michèle, Cheng, Joanna, Edey, Lydia, Robson, Stephen C., Ulrich, Scott M., Treumann, Achim, Taggart, Michael J., Europe-Finner, G. Nicholas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.09.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation; Acetylation - drug effects; Actin Depolymerizing Factors - metabolism; Cell Biology; Cell Nucleus - metabolism; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Cytoskeleton; Female; Heat Shock Protein; Histone Deacetylase; Histone Deacetylase Inhibitors; Histone Deacetylases - metabolism; Histones - metabolism; Hsp20; HSP20 Heat-Shock Proteins - metabolism; Humans; Myometrium; Myometrium - cytology; Myometrium - metabolism; Myometrium - physiology; Oxytocics - pharmacology; Oxytocin - pharmacology; Phosphorylation - drug effects; Phosphorylation - physiology; Protein Processing, Post-Translational; Repressor Proteins - metabolism; Smooth Muscle; Uterine Contraction - drug effects; Uterine Contraction - physiology; Myometrium; Cytoskeleton; Histone Deacetylase Inhibitors; Acetylation; Smooth Muscle; Heat Shock Protein; Histone Deacetylase; Hsp20
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M111.278549

Phosphorylation of heat shock protein 20 (Hsp20) by protein kinase A (PKA) is now recognized as an important regulatory mechanism modulating contractile activity in the human myometrium. Thus agonists that stimulate cyclic AMP production may cause relaxation with resultant beneficial effects on pathologies that affect this tissue such as the onset of premature contractions prior to term. Here we describe for the first time that acetylation of Hsp20 is also a potent post-translational modification that can affect human myometrial activity. We show that histone deacetylase 8 (HDAC8) is a non-nuclear lysine deacetylase (KDAC) that can interact with Hsp20 to affect its acetylation. Importantly, use of a selective linkerless hydroxamic acid HDAC8 inhibitor increases Hsp20 acetylation with no elevation of nuclear-resident histone acetylation nor marked global gene expression changes. These effects are associated with significant inhibition of spontaneous and oxytocin-augmented contractions of ex vivo human myometrial tissue strips. A potential molecular mechanism by which Hsp20 acetylation can affect myometrial activity by liberating cofilin is described and further high-lights the use of specific effectors of KDACs as therapeutic agents in regulating contractility in this smooth muscle.