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Journal of Virology, July 2004, p. 6744-6757, Vol. 78, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.13.6744-6757.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Functional Interaction between Class II Histone Deacetylases and ICP0 of Herpes Simplex Virus Type 1

Equipe Silencing Viral et Remodelage de la Chromatine,¹ Equipe Génétique Moléculaire du virus Herpes Simplex de Type 1, Centre de Génétique Moléculaire et Cellulaire, UMR5534-CNRS, Université Claude Bernard Lyon 1, 69622 Villeurbanne Cedex,² Equipe Chromatine et Expression des Gènes, Laboratoire de Biologie Moléculaire et Cellulaire de la Différenciation, INSERM U309, Institut Albert Bonniot, Faculté de Médecine, Domaine de la Merci, 38706 La Tronche Cedex, France³

Received 8 December 2003/ Accepted 27 February 2004

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.

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