Disruption of HDAC/CoREST/REST repressor by dnREST reduces genome silencing and increases virulence of herpes simplex virus
Disruption of HDAC/CoREST/REST repressor by dnREST reduces genome silencing and increases virulence of herpes simplex virus
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DOI：
10.1073/pnas.1010741107
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发表时间：
2010-09-07
影响因子：
11.1
通讯作者：
Roizman, Bernard
中科院分区：
文献类型：
--
作者：
Du, Te;Zhou, Guoying;Roizman, Bernard
在非神经元细胞中，单纯疱疹病毒1型克服宿主防御，复制并最终杀死被感染的细胞。在被病毒抑制的宿主防御中，有一种阻遏物复合物，其关键成分是组蛋白脱乙酰酶（HDAC）1或2、RE-1沉默转录因子（REST）、REST辅阻遏物（CoREST）和赖氨酸特异性脱甲基酶（LSD）1。在进入体内的入口处神经元支配细胞中，病毒建立了一种“潜伏”感染，其中病毒DNA被沉默，只有一个基因家族除外。这里提出的问题是，病毒是否劫持了这种阻遏物复合物，在潜伏状态下使神经元中的自身沉默。为了验证这一假设，我们在野生型病毒基因组中插入了野生型REST [重组体（R）111]、缺少N-和C-末端阻遏结构域的显性负性REST（dnREST）（R112）或由终止密码子串联重复序列组成的插入对照（R113）。携带dnREST的重组病毒R112复制得更好，并且当通过角膜或i. p.途径给药时，比野生型亲本或其他重组病毒更具毒性。此外，与其他重组体相比，通过R112重组病毒的角膜途径接种导致更高的DNA拷贝数，眼、三叉神经节或脑中更高水平的感染性病毒，并且小鼠三叉神经节几乎完全破坏，最终可能死于感染。这些结果支持了早期的结论，即HDAC/CoREST/REST/LSD 1阻遏物复合物是宿主先天免疫的重要组成部分，并且与HSV-1在潜伏感染期间劫持阻遏物使其自身沉默的假设一致。
Innonneuronal cells, herpes simplexvirus 1 overcomes host defenses, replicates, and ultimately kills the infected cell. Among the host defenses suppressed by the virus is a repressor complex whose key components are histone deacetylase (HDAC) 1 or 2, RE-1 silencing transcription factor (REST), corepressor of REST (CoREST), and lysine-specific demethylase (LSD) 1. In neurons innervating cells at the portal of entry into the body, the virus establishes a "latent" infection in which viral DNA is silenced with the exception of a family of genes. The question posed here is whether the virus hijacks this repressor complex to silence itself in neurons during the latent state. To test this hypothesis, we inserted into the wild-type virus genome a wild-type REST [recombinant (R) 111], a dominant-negative REST (dnREST) lacking the N- and C-terminal repressor domains (R112), or an insertion control consisting of tandem repeats of stop codons (R113). The recombinant virus R112 carrying the dnREST replicated better and was more virulent than the wild-type parent or the other recombinant viruses when administered by the corneal or i.p. routes. Moreover, in contrast to other recombinants, corneal route inoculation by R112 recombinant virus resulted in higher DNA copy numbers, higher levels of infectious virus in eye, trigeminal ganglion, or brain, and virtually complete destruction of trigeminal ganglia in mice that may ultimately succumb to infection. These results support an earlier conclusion that the HDAC/CoREST/REST/LSD1 repressor complex is a significant component of the host innate immunity and are consistent with the hypothesis that HSV-1 hijacks the repressor to silence itself during latent infection.