Nuclear translocation of NF-κB precedes apoptotic poly(ADP-ribose) polymerase cleavage during productive HSV-1 replication in corneal epithelial cells

Margot L. Goodkin, Seth Epstein, Penny Asbell, John A. Blaho

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

PURPOSE. Herpes simplex virus (HSV)-1 infections of the human cornea range in severity from uncomplicated episodes that readily resolve to severe, recurring disease that invades the stroma, having a devastating permanent effect on vision. Recent published data implicate an apoptotic component to stromal HSV-1 infection. In a prior study, it was found that wild type (wt) HSV-1 infection induces, then blocks, apoptosis in epithelial cells derived from skin and that this block requires infected cell proteins (ICPs) synthesized between 3 and 6 hours post infection (hpi). This inhibition of apoptosis is in part dependent on the activation of inducible nuclear transcription factor κB (NF-κB). METHODS. HSV-1-dependent apoptosis in rabbit corneal epithelial (SIRC) cells was compared with that in infected human epithelial (HEp-2) cells. RESULTS. SIRC cells were sensitive to apoptotic cell death induced by environmental treatment with tumor necrosis factor (TNF)-α plus cycloheximide (CHX). HSV-1 stimulated the degradation of regulatory IκBα protein, resulting in nuclear translocation of NF-κB. This phenomenon was dependent on ICP synthesis. Neither wt nor apoptotic HSV-1 infection resulted in apoptosis in these cells. However, wt HSV-1-infected cells produced detectable levels of cleaved poly(ADP-ribose) (PARP). Inhibition of SIRC cell protein synthesis with CHX during wt HSV-1 infection led to a reduction in the amount of PARP cleavage. Whereas PARP cleavage defined cell death in most other cell types, its processing in SIRC cells was a reproducible characteristic of wt HSV-1 infection. CONCLUSIONS. This is the first report of such an effect, and it suggests that in corneal epithelial cells, activation of apoptotic pathways may be necessary for productive viral replication. Thus, efficient replication of HSV-1 in the corneal milieu proceeds via a different mechanism than it does in skin. However, it appears that NF-κB participates in inhibiting apoptosis during HSV-1 infection in both systems.

Original languageEnglish (US)
Pages (from-to)4980-4988
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number11
DOIs
StatePublished - Nov 1 2007

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Poly(ADP-ribose) Polymerases
Human Herpesvirus 1
Virus Replication
Virus Diseases
Transcription Factors
Epithelial Cells
Apoptosis
Simplexvirus
Cycloheximide
Proteins
Cell Death
Poly Adenosine Diphosphate Ribose
Skin
Cornea
Tumor Necrosis Factor-alpha
Rabbits

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Nuclear translocation of NF-κB precedes apoptotic poly(ADP-ribose) polymerase cleavage during productive HSV-1 replication in corneal epithelial cells. / Goodkin, Margot L.; Epstein, Seth; Asbell, Penny; Blaho, John A.

In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 11, 01.11.2007, p. 4980-4988.

Research output: Contribution to journalArticle

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abstract = "PURPOSE. Herpes simplex virus (HSV)-1 infections of the human cornea range in severity from uncomplicated episodes that readily resolve to severe, recurring disease that invades the stroma, having a devastating permanent effect on vision. Recent published data implicate an apoptotic component to stromal HSV-1 infection. In a prior study, it was found that wild type (wt) HSV-1 infection induces, then blocks, apoptosis in epithelial cells derived from skin and that this block requires infected cell proteins (ICPs) synthesized between 3 and 6 hours post infection (hpi). This inhibition of apoptosis is in part dependent on the activation of inducible nuclear transcription factor κB (NF-κB). METHODS. HSV-1-dependent apoptosis in rabbit corneal epithelial (SIRC) cells was compared with that in infected human epithelial (HEp-2) cells. RESULTS. SIRC cells were sensitive to apoptotic cell death induced by environmental treatment with tumor necrosis factor (TNF)-α plus cycloheximide (CHX). HSV-1 stimulated the degradation of regulatory IκBα protein, resulting in nuclear translocation of NF-κB. This phenomenon was dependent on ICP synthesis. Neither wt nor apoptotic HSV-1 infection resulted in apoptosis in these cells. However, wt HSV-1-infected cells produced detectable levels of cleaved poly(ADP-ribose) (PARP). Inhibition of SIRC cell protein synthesis with CHX during wt HSV-1 infection led to a reduction in the amount of PARP cleavage. Whereas PARP cleavage defined cell death in most other cell types, its processing in SIRC cells was a reproducible characteristic of wt HSV-1 infection. CONCLUSIONS. This is the first report of such an effect, and it suggests that in corneal epithelial cells, activation of apoptotic pathways may be necessary for productive viral replication. Thus, efficient replication of HSV-1 in the corneal milieu proceeds via a different mechanism than it does in skin. However, it appears that NF-κB participates in inhibiting apoptosis during HSV-1 infection in both systems.",
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N2 - PURPOSE. Herpes simplex virus (HSV)-1 infections of the human cornea range in severity from uncomplicated episodes that readily resolve to severe, recurring disease that invades the stroma, having a devastating permanent effect on vision. Recent published data implicate an apoptotic component to stromal HSV-1 infection. In a prior study, it was found that wild type (wt) HSV-1 infection induces, then blocks, apoptosis in epithelial cells derived from skin and that this block requires infected cell proteins (ICPs) synthesized between 3 and 6 hours post infection (hpi). This inhibition of apoptosis is in part dependent on the activation of inducible nuclear transcription factor κB (NF-κB). METHODS. HSV-1-dependent apoptosis in rabbit corneal epithelial (SIRC) cells was compared with that in infected human epithelial (HEp-2) cells. RESULTS. SIRC cells were sensitive to apoptotic cell death induced by environmental treatment with tumor necrosis factor (TNF)-α plus cycloheximide (CHX). HSV-1 stimulated the degradation of regulatory IκBα protein, resulting in nuclear translocation of NF-κB. This phenomenon was dependent on ICP synthesis. Neither wt nor apoptotic HSV-1 infection resulted in apoptosis in these cells. However, wt HSV-1-infected cells produced detectable levels of cleaved poly(ADP-ribose) (PARP). Inhibition of SIRC cell protein synthesis with CHX during wt HSV-1 infection led to a reduction in the amount of PARP cleavage. Whereas PARP cleavage defined cell death in most other cell types, its processing in SIRC cells was a reproducible characteristic of wt HSV-1 infection. CONCLUSIONS. This is the first report of such an effect, and it suggests that in corneal epithelial cells, activation of apoptotic pathways may be necessary for productive viral replication. Thus, efficient replication of HSV-1 in the corneal milieu proceeds via a different mechanism than it does in skin. However, it appears that NF-κB participates in inhibiting apoptosis during HSV-1 infection in both systems.

AB - PURPOSE. Herpes simplex virus (HSV)-1 infections of the human cornea range in severity from uncomplicated episodes that readily resolve to severe, recurring disease that invades the stroma, having a devastating permanent effect on vision. Recent published data implicate an apoptotic component to stromal HSV-1 infection. In a prior study, it was found that wild type (wt) HSV-1 infection induces, then blocks, apoptosis in epithelial cells derived from skin and that this block requires infected cell proteins (ICPs) synthesized between 3 and 6 hours post infection (hpi). This inhibition of apoptosis is in part dependent on the activation of inducible nuclear transcription factor κB (NF-κB). METHODS. HSV-1-dependent apoptosis in rabbit corneal epithelial (SIRC) cells was compared with that in infected human epithelial (HEp-2) cells. RESULTS. SIRC cells were sensitive to apoptotic cell death induced by environmental treatment with tumor necrosis factor (TNF)-α plus cycloheximide (CHX). HSV-1 stimulated the degradation of regulatory IκBα protein, resulting in nuclear translocation of NF-κB. This phenomenon was dependent on ICP synthesis. Neither wt nor apoptotic HSV-1 infection resulted in apoptosis in these cells. However, wt HSV-1-infected cells produced detectable levels of cleaved poly(ADP-ribose) (PARP). Inhibition of SIRC cell protein synthesis with CHX during wt HSV-1 infection led to a reduction in the amount of PARP cleavage. Whereas PARP cleavage defined cell death in most other cell types, its processing in SIRC cells was a reproducible characteristic of wt HSV-1 infection. CONCLUSIONS. This is the first report of such an effect, and it suggests that in corneal epithelial cells, activation of apoptotic pathways may be necessary for productive viral replication. Thus, efficient replication of HSV-1 in the corneal milieu proceeds via a different mechanism than it does in skin. However, it appears that NF-κB participates in inhibiting apoptosis during HSV-1 infection in both systems.

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