TY - JOUR
T1 - Activation of NF-κB in cells productively infected with HSV-1 depends on activated protein kinase R and plays no apparent role in blocking apoptosis
AU - Taddeo, Brunella
AU - Luo, Ting Rong
AU - Zhang, Weiran
AU - Roizman, Bernard
PY - 2003/10/14
Y1 - 2003/10/14
N2 - Microarray data reported elsewhere indicated that herpes simplex virus 1 induces the up-regulation of nuclear factor κB (NF-κB)-regulated genes, including that of its inhibitor, IκBα, consistent with the reports that wild-type virus induces the activation of NF-κB. In this report we show that activation of NF-κB 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 γ134.5, which encodes a protein phosphatase 1α accessory factor that enables the dephosphorylation of the α subunit of eukaryotic translation initiation factor 2. NF-κB is activated in wild-type murine embryonic fibroblasts but not in related PKR-null cells. (ii) In cells infected with a replication-competent Δγ134.5 mutant (R5104), but carrying a Us11 gene expressed early in infection, eukaryotic translation initiation factor 2α 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 IκBα, and does not cause the translocation of NF-κB in infected cells. (iii) One hypothesis advanced for the activation of NF-κB 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-κB depends on activation of PKR and that NF-κB is not required to block apoptosis in productively infected cells.
AB - Microarray data reported elsewhere indicated that herpes simplex virus 1 induces the up-regulation of nuclear factor κB (NF-κB)-regulated genes, including that of its inhibitor, IκBα, consistent with the reports that wild-type virus induces the activation of NF-κB. In this report we show that activation of NF-κB 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 γ134.5, which encodes a protein phosphatase 1α accessory factor that enables the dephosphorylation of the α subunit of eukaryotic translation initiation factor 2. NF-κB is activated in wild-type murine embryonic fibroblasts but not in related PKR-null cells. (ii) In cells infected with a replication-competent Δγ134.5 mutant (R5104), but carrying a Us11 gene expressed early in infection, eukaryotic translation initiation factor 2α 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 IκBα, and does not cause the translocation of NF-κB in infected cells. (iii) One hypothesis advanced for the activation of NF-κB 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-κB depends on activation of PKR and that NF-κB is not required to block apoptosis in productively infected cells.
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U2 - 10.1073/pnas.2034952100
DO - 10.1073/pnas.2034952100
M3 - Article
C2 - 14530405
AN - SCOPUS:0142027749
SN - 0027-8424
VL - 100
SP - 12408
EP - 12413
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -