Histone deacetylases and the nuclear receptor corepressor regulate lytic-latent switch gene 50 in murine gammaherpesvirus 68-infected macrophages.
Gammaherpesviruses are important oncogenic pathogens that transit between lytic and latent life cycles. Silencing the lytic gene expression program enables the establishment of latency and a lifelong chronic infection of the host. In murine gammaherpesvirus 68 (MHV68, γHV68), essential lytic switch gene 50 controls the interchange between lytic and latent gene expression programs. However, negative regulators of gene 50 expression remain largely undefined. We report that the MHV68 lytic cycle is silenced in infected macrophages but not fibroblasts and that histone deacetylases (HDACs) mediate silencing. The HDAC inhibitor trichostatin A (TSA) acts on the gene 50 promoter to induce lytic replication of MHV68. HDAC3, HDAC4, and the nuclear receptor corepressor (NCoR) are required for efficient silencing of gene 50 expression. NCoR is critical for transcriptional repression of cellular genes by unliganded nuclear receptors. Retinoic acid, a known ligand for the NCoR complex, derepresses gene 50 expression and enhances MHV68 lytic replication. Moreover, HDAC3, HDAC4, and NCoR act on the gene 50 promoter and are recruited to this promoter in a retinoic acid-responsive manner. We provide the first example of NCoR-mediated, HDAC-dependent regulation of viral gene expression.
Goodwin
Megan M
MM
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
Molleston
Jerome M
JM
Canny
Susan
S
Abou El Hassan
Mohamed
M
Willert
Erin K
EK
Bremner
Rod
R
Virgin
Herbert W
HW
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018142:Gammaherpesvirinae / Q000235:genetics / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D006566:Herpesviridae Infections / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D051379:Mice; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency; D014779:Virus Replication; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D017874:Immediate-Early Proteins; D056971:Nuclear Receptor Co-Repressor 1; D015534:Trans-Activators; D000099186:Histone Deacetylase 3; C539128:Ncor1 protein, mouse; C404327:gene 50 protein, gammaherpesvirus 68; C498618:Hdac5 protein, mouse