Herpes simplex type 1 induction of persistent NF-kappa B nuclear translocation increases the efficiency of virus replication.
The latent form of the dimeric transcription factor NF-kappa B is sequestered in the cytoplasm by proteins containing ankyrin repeats, such as 1 kappa B alpha and beta, or by the p105 precursor form of the NF-kappa B p50 subunit. Tumor necrosis factor alpha or virus infection can cause targeted destruction of 1 kappa B and nuclear translocation of NF-kappa B. Following translocation, NF-kappa B mediates immune, inflammatory, or anti-apoptotic responses. Here we present evidence that beginning at around 6 h postinfection, herpes simplex virus (HSV) induces a persistent translocation of NF-kappa B into the nucleus of C33 cells, coincident with loss of both 1 kappa B alpha and 1 kappa B beta. Translocation failed to occur when infecting virus was preincubated with neutralizing antibody to viral envelope glycoproteins gD or gH, thus preventing entry, or when cells infected with viruses expressing mutated forms of immediate-early regulatory proteins lCP4 or lCP27. Surprisingly, no increase in the trans-activation function of NF-kappa B, as assayed by transient expression of CAT, was detected following HSV infection. The significance of NF-kappa B nuclear translocation for virus replication was demonstrated by an 80-90% reduction in virus yield following infection of C33 cells expressing a constitutive repressor form of 1 kappa B alpha. Models that reconcile nuclear translocation of NF-kappa B with the inability to detect NF-kappa B-dependent gene expression are discussed.
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill 27599, USA.
A
A
Patel
J
J
Hanson
T I
TI
McLean
J
J
Olgiate
M
M
Hilton
W E
WE
Miller
S L
SL
Bachenheimer
D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; C057120:ICP27 protein, human herpesvirus 1; D017874:Immediate-Early Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012097:Repressor Proteins; C048925:herpes simplex virus, type 1 protein ICP4; D000072000:NF-KappaB Inhibitor alpha