Epstein-Barr virus lytic infection induces retinoic acid-responsive genes through induction of a retinol-metabolizing enzyme, DHRS9.
Lytic Epstein-Barr virus (EBV) replication occurs in differentiated, but not undifferentiated, epithelial cells. Retinoic acid (RA) induces epithelial cell differentiation. The conversion of retinol into its active form, retinoic acid, requires retinol dehydrogenase enzymes. Here we show that AGS gastric carcinoma cells containing the lytic form of EBV infection have enhanced expression of a gene (DHRS9) encoding an enzyme that mediates conversion of retinol into RA. DHRS9 expression is also increased following induction of lytic viral infection in EBV-positive Burkitt lymphoma cells. We demonstrate that the EBV immediate-early protein, BZLF1, activates the DHRS9 promoter through a direct DNA binding mechanism. Furthermore, BZLF1 expression in AGS cells is sufficient to activate DHRS9 gene expression and increases the ability of retinol to induce the RA-responsive gene, CYP26A1. Production of RA during the lytic form of EBV infection may enhance viral replication by promoting keratinocyte differentiation.
Jones
Richard J
RJ
Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27514, USA.
Dickerson
Sarah
S
Bhende
Prassana M
PM
Delecluse
Henri-Jacque
HJ
Kenney
Shannon C
SC
D015096:3-Hydroxysteroid Dehydrogenases; D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D002051:Burkitt Lymphoma / Q000378:metabolism / Q000821:virology*; D002213:Capsid / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000821:virology; D000072516:Retinoic Acid 4-Hydroxylase; D014212:Tretinoin / Q000378:metabolism*; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication; D014801:Vitamin A / Q000378:metabolism*
D007074:Immunoglobulin G; D014801:Vitamin A; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D015096:3-Hydroxysteroid Dehydrogenases; C432414:DHRS9 protein, human; D000426:Alcohol Dehydrogenase; D000072516:Retinoic Acid 4-Hydroxylase