Activation of NF-kappaB in cells productively infected with HSV-1 depends on activated protein kinase R and plays no apparent role in blocking apoptosis.
Microarray data reported elsewhere indicated that herpes simplex virus 1 induces the up-regulation of nuclear factor kappaB (NF-kappaB)-regulated genes, including that of its inhibitor, IkappaBalpha, consistent with the reports that wild-type virus induces the activation of NF-kappaB. In this report we show that activation of NF-kappaB in infected cells is linked to the activation of protein kinase R (PKR). Specifically: (i) PKR is activated in infected cells although the effects of the activated enzyme on protein synthesis are negated by the viral gene gamma134.5, which encodes a protein phosphatase 1alpha accessory factor that enables the dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. NF-kappaB is activated in wild-type murine embryonic fibroblasts but not in related PKR-null cells. (ii) In cells infected with a replication-competent Deltagamma134.5 mutant (R5104), but carrying a US11 gene expressed early in infection, eukaryotic translation initiation factor 2alpha is not phosphorylated, and in in vitro assays, PKR bound to the US11 protein is not phosphorylated on subsequent addition of double-stranded RNA. Here we report that this mutant does not activate PKR, has no effect on the accumulation of IkappaBalpha, and does not cause the translocation of NF-kappaB in infected cells. (iii) One hypothesis advanced for the activation of NF-kappaB is that it blocks apoptosis induced by viral gene products. The replication-competent R5104 mutant does not induce the programmed cell's death. We conclude that in herpes simplex virus 1-infected cells, activation of NF-kappaB depends on activation of PKR and that NF-kappaB is not required to block apoptosis in productively infected cells.
Taddeo
Brunella
B
The Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, 910 East 58th Street, Chicago, IL 60637, USA.
Luo
Ting Rong
TR
Zhang
Weiran
W
Roizman
Bernard
B
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D005814:Genes, Viral; D006561:Herpes Simplex / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse