title: Acetylation of heat shock protein 20 (Hsp20) regulates human myometrial activity.
abstract: 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.
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom. magda.karolczak@ncl.ac.uk
authors.forename: Magdalena
authors.initials: M
authors.lastname: Karolczak-Bayatti
authors.forename: Michèle
authors.initials: M
authors.lastname: Sweeney
authors.forename: Joanna
authors.initials: J
authors.lastname: Cheng
authors.forename: Lydia
authors.initials: L
authors.lastname: Edey
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Robson
authors.forename: Scott M
authors.initials: SM
authors.lastname: Ulrich
authors.forename: Achim
authors.initials: A
authors.lastname: Treumann
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Taggart
authors.forename: G Nicholas
authors.initials: GN
authors.lastname: Europe-Finner
mesh_terms: D000107:Acetylation / Q000187:drug effects; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009215:Myometrium / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*; D010120:Oxytocics / Q000494:pharmacology; D010121:Oxytocin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000378:metabolism; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology*
chemical_list: D051339:Actin Depolymerizing Factors; D050886:HSP20 Heat-Shock Proteins; C494382:HSPB6 protein, human; D006657:Histones; D010120:Oxytocics; D012097:Repressor Proteins; D010121:Oxytocin; D017868:Cyclic AMP-Dependent Protein Kinases; C409470:HDAC8 protein, human; D006655:Histone Deacetylases