Activation of host antiviral RNA-sensing factors necessary for herpes simplex virus type 1-activated transcription of host cell fucosyltransferase genes FUT3, FUT5, and FUT6 and subsequent expression of sLe(x) in virus-infected cells.
Herpes simplex virus type 1 (HSV-1) induces expression of a selectin receptor, the carbohydrate epitope sialyl Lewis X (sLe(x)), at the surface of infected cells. The molecular background to this phenomenon is that a viral immediate early RNA interacts with as yet unidentified host factors, eventually resulting in transcription of three dormant host fucosyltransferase genes (FUT3, FUT5, and FUT6), whose gene products are rate-limiting for synthesis of sLe(x). The aim of the present study was to define the immediate targets for the viral RNA in this process. We found that the Protein Kinase R (PKR) inhibitors 2-aminopurine (2-AP) and C16 inhibited FUT3, FUT5, and FUT6 expression as well as HSV-1-induced expression of sLe(x), indicating a primary role of PKR as a viral RNA target. The PKR-dependent activation of the FUT genes seemed neither to involve PKR effects on translation nor to involve NF-kappaB- or JNK-dependent activation. IMD-0354, known as an inhibitor of the NF-kappaB-activating factor IKK-2, induced FUT transcription via a novel IKK-2-independent mechanism, irrespective of whether the cells were virus-infected or not. Altogether, the results suggested that PKR is the primary target for HSV-1 early RNA during induction of FUT3, FUT5, and FUT6, and that the subsequent steps in the transcriptional activation of these host genes involve a hitherto unknown IMD-0354, yet IKK-2-independent, pathway.
Nordén
Rickard
R
Department of Virology, University of Gothenburg, Gothenburg, Sweden.
Nyström
Kristina
K
Olofsson
Sigvard
S
D015075:2-Aminopurine / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D005647:Fucosyltransferases / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D006801:Humans; D016256:Lewis X Antigen / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D019892:eIF-2 Kinase / Q000378:metabolism*
D001549:Benzamides; D016256:Lewis X Antigen; D015075:2-Aminopurine; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D005647:Fucosyltransferases; D019892:eIF-2 Kinase