Herpes simplex virus 1 infection activates poly(ADP-ribose) polymerase and triggers the degradation of poly(ADP-ribose) glycohydrolase.

Abstract

Herpes simplex virus 1 infection triggers multiple changes in the metabolism of host cells, including a dramatic decrease in the levels of NAD(+). In addition to its role as a cofactor in reduction-oxidation reactions, NAD(+) is required for certain posttranslational modifications. Members of the poly(ADP-ribose) polymerase (PARP) family of enzymes are major consumers of NAD(+), which they utilize to form poly(ADP-ribose) (PAR) chains on protein substrates in response to DNA damage. PAR chains can subsequently be removed by the enzyme poly(ADP-ribose) glycohydrolase (PARG). We report here that the HSV-1 infection-induced drop in NAD(+) levels required viral DNA replication, was associated with an increase in protein poly(ADP-ribosyl)ation (PARylation), and was blocked by pharmacological inhibition of PARP-1/PARP-2 (PARP-1/2). Neither virus yield nor the cellular metabolic reprogramming observed during HSV-1 infection was altered by the rescue or further depletion of NAD(+) levels. Expression of the viral protein ICP0, which possesses E3 ubiquitin ligase activity, was both necessary and sufficient for the degradation of the 111-kDa PARG isoform. This work demonstrates that HSV-1 infection results in changes to NAD(+) metabolism by PARP-1/2 and PARG, and as PAR chain accumulation can induce caspase-independent apoptosis, we speculate that the decrease in PARG levels enhances the auto-PARylation-mediated inhibition of PARP, thereby avoiding premature death of the infected cell.

• Authors: Sarah L Grady, Jesse Hwang, Livia Vastag, Joshua D Rabinowitz, Thomas Shenk
• Journal: Journal of virology (J Virol) Vol. 86 Issue 15 Pg. 8259-68 (Aug 2012) ISSN: 1098-5514 [Electronic] United States
• PMID: 22623791 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• DNA, Viral
• Immediate-Early Proteins
• NAD
• Ubiquitin-Protein Ligases
• Vmw110 protein, Human herpesvirus 1
• PARP1 protein, human
• PARP2 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Glycoside Hydrolases
• poly ADP-ribose glycohydrolase

Topics

• Cells, Cultured
• DNA Replication (genetics)
• DNA, Viral (genetics, metabolism)
• Glycoside Hydrolases (genetics, metabolism)
• Herpes Simplex (enzymology, genetics)
• Herpesvirus 1, Human (genetics, metabolism)
• Humans
• Immediate-Early Proteins (genetics, metabolism)
• NAD (genetics, metabolism)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Proteolysis
• Ubiquitin-Protein Ligases (genetics, metabolism)