title: Functional interaction between class II histone deacetylases and ICP0 of herpes simplex virus type 1.
abstract: This study describes the physical and functional interactions between ICP0 of herpes simplex virus type 1 and class II histone deacetylases (HDACs) 4, 5, and 7. Class II HDACs are mainly known for their participation in the control of cell differentiation through the regulation of the activity of the transcription factor MEF2 (myocyte enhancer factor 2), implicated in muscle development and neuronal survival. Immunofluorescence experiments performed on transfected cells showed that ICP0 colocalizes with and reorganizes the nuclear distribution of ectopically expressed class I and II HDACs. In addition, endogenous HDAC4 and at least one of its binding partners, the corepressor protein SMRT (for silencing mediator of retinoid and thyroid receptor), undergo changes in their nuclear distribution in ICP0-transfected cells. As a result, during infection endogenous HDAC4 colocalizes with ICP0. Coimmunoprecipitation and glutathione S-transferase pull-down assays confirmed that class II but not class I HDACs specifically interacted with ICP0 through their amino-terminal regions. This region, which is not conserved in class I HDACs but homologous to the MITR (MEF2-interacting transcription repressor) protein, is responsible for the repression, in a deacetylase-independent manner, of MEF2 by sequestering it under an inactive form in the nucleus. Consequently, we show that ICP0 is able to overcome the HDAC5 amino-terminal- and MITR-induced MEF2A repression in gene reporter assays. This is the first report of a viral protein interacting with and controlling the repressor activity of class II HDACs. We discuss the putative consequences of such an interaction for the biology of the virus both during lytic infection and reactivation from latency.
authors.affiliation: Equipe Silencing Viral et Remodelage de la Chromatine, Centre de Génétique Moléculaire et Cellulaire, UMR5534-CNRS, Université Claude Bernard Lyon 1, 69622 Villeurbanne Cedex, France. lomonte@cgmc.univ-lyon1.fr
authors.forename: Patrick
authors.initials: P
authors.lastname: Lomonte
authors.forename: Joëlle
authors.initials: J
authors.lastname: Thomas
authors.forename: Pascale
authors.initials: P
authors.lastname: Texier
authors.forename: Cécile
authors.initials: C
authors.lastname: Caron
authors.forename: Saadi
authors.initials: S
authors.lastname: Khochbin
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Epstein
mesh_terms: D000818:Animals; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D012097:Repressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D017874:Immediate-Early Proteins; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; C543273:HDAC7 protein, human; D006655:Histone Deacetylases