Herpes Simplex Virus 1 Infection Activates Poly(ADP-Ribose) Polymerase and Triggers the Degradation of Poly(ADP-Ribose) Glycohydrolase
Herpes Simplex Virus 1 Infection Activates Poly(ADP-Ribose) Polymerase and Triggers the Degradation of Poly(ADP-Ribose) Glycohydrolase
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DOI：
10.1128/jvi.00495-12
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发表时间：
2012-08-01
影响因子：
5.4
通讯作者：
Shenk, Thomas
中科院分区：
文献类型：
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作者：
Grady, Sarah L.;Hwang, Jesse;Shenk, Thomas
单纯疱疹病毒1型感染引发宿主细胞代谢的多种变化，包括NAD（+）水平的急剧下降。除了在还原-氧化反应中作为辅助因子外，NAD（+）在某些翻译后修饰中也是必需的。聚（adp -核糖）聚合酶（PARP）家族的成员是NAD（+）的主要消费者，它们利用NAD（+）在蛋白质底物上形成聚（adp -核糖）（PAR）链，以响应DNA损伤。PAR链随后可被聚（adp -核糖）糖水解酶（PARG）去除。我们在这里报道了HSV-1感染诱导的NAD（+）水平的下降需要病毒DNA复制，与蛋白质聚（adp -核糖基）化（PARylation）的增加有关，并被PARP-1/PARP-2 （PARP-1/2）的药物抑制所阻断。在HSV-1感染期间观察到的病毒产量和细胞代谢重编程都不会因挽救或进一步消耗NAD（+）水平而改变。具有E3泛素连接酶活性的病毒蛋白ICP0的表达是降解111-kDa PARG亚型的必要和充分条件。本研究表明，HSV-1感染可导致PARP-1/2和PARG对NAD（+）代谢的改变，并且由于PAR链积累可诱导caspase非依赖性细胞凋亡，我们推测PARG水平的降低可增强PARP自聚合介导的抑制作用，从而避免被感染细胞的过早死亡。
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.