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Herpes simplex virus 1 infection activates poly(ADP-ribose) polymerase and triggers the degradation of poly(ADP-ribose) glycohydrolase.
Grady, Sarah L; Hwang, Jesse; Vastag, Livia; Rabinowitz, Joshua D; Shenk, Thomas.
Afiliação
  • Grady SL; Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
J Virol ; 86(15): 8259-68, 2012 Aug.
Article em En | MEDLINE | ID: mdl-22623791
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Poli(ADP-Ribose) Polimerases / Herpesvirus Humano 1 / Proteólise / Glicosídeo Hidrolases / Herpes Simples Limite: Humans Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Poli(ADP-Ribose) Polimerases / Herpesvirus Humano 1 / Proteólise / Glicosídeo Hidrolases / Herpes Simples Limite: Humans Idioma: En Ano de publicação: 2012 Tipo de documento: Article