Promyelocytic leukemia (PML) nuclear bodies (NBs) induce latent/quiescent HSV-1 genomes chromatinization through a PML NB/Histone H3.3/H3.3 Chaperone Axis.
Promyelocytic leukemia (PML) nuclear bodies (NBs) induce latent/quiescent HSV-1 genomes chromatinization through a PML NB/Histone H3.3/H3.3 Chaperone Axis.
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DOI：
10.1371/journal.ppat.1007313
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发表时间：
2018-09
期刊：
影响因子：
6.7
通讯作者：
Lomonte P
中科院分区：
文献类型：
--
作者：
Cohen C;Corpet A;Roubille S;Maroui MA;Poccardi N;Rousseau A;Kleijwegt C;Binda O;Texier P;Sawtell N;Labetoulle M;Lomonte P
单纯疱疹病毒 1 (HSV-1) 潜伏期的建立受到早幼粒细胞白血病 (PML) 核体 (NB)（或 ND10）的严格控制，尽管它们的确切贡献仍然难以捉摸。 HSV-1潜伏期的一个标志是潜伏病毒基因组和PML NB之间的相互作用，导致含有病毒DNA的PML NB（vDCP NB）的形成，以及HSV-1的完全沉默。使用复制缺陷型 HSV-1 感染的人原代成纤维细胞模型再现 vDCP NB 的形成，并结合开发用于检测潜伏/静止 HSV-1 的免疫 FISH 方法，我们发现 vDCP NB 包含组蛋白 H3.3 及其伴侣复合物，即 DAXX/ATRX 和 HIRA 复合物（HIRA、UBN1、CABIN1 和 ASF1a）。 HIRA 还与 HSV-1 感染的野生型小鼠的三叉神经节 (TG) 神经元中存在的 vDCP NB 共定位。 ChIP 和 Re-ChIP 显示，vDCP NB 相关的潜伏/静止病毒基因组几乎完全由通过三甲基化对其赖氨酸 (K) 9 进行修饰的 H3.3 进行染色质化，这与 H3.3 伴侣与多个病毒位点以及 HSV-1 转录沉默的相互作用一致。只有两个 H3.3 伴侣复合物同时失活才会对 H3.3 在病毒基因组上的沉积产生显着影响，这表明存在补偿机制。相比之下，PML 的单独缺失显着影响 H3.3 的潜伏/静止病毒基因组的染色质化，而无需用 H3.1 进行任何整体替换。 vDCP NB 相关的 HSV-1 基因组并未被彻底沉默，因为 ICP0 使 vDCP NB 不稳定（这对于体内 HSV-1 重新激活至关重要），从而允许转录裂解程序的恢复和病毒基因组的复制。因此，本研究表明，通过涉及两个 H3.3 分子伴侣 DAXX/ATRX 和 HIRA 复合物的 H3.3 依赖性 HSV-1 染色质化，对 vDCP NB 相关的潜伏/静止 HSV-1 进行特异性染色质调节。此外，该研究还表明，PML NB 通过 PML NB/组蛋白 H3.3/H3.3 伴侣轴在潜伏/静态 HSV-1 H3.3 染色质化中起主要作用。了解病毒在宿主体内持久存在的分子机制对于控制病毒再激活及其相关疾病至关重要。单纯疱疹病毒 1 (HSV-1) 是一种人类病原体，潜伏在受感染宿主的 PNS 和 CNS 中。潜伏期不稳定，病毒的频繁重新激活是造成三七总皂甙和中枢神经系统病理的原因。因此，了解潜伏 HSV-1 与宿主之间相互作用的生理、免疫和分子水平至关重要。早幼粒细胞白血病 (PML) 核体 (NB) 通过预防溶解性感染的发生来控制病毒感染。在之前的研究中，我们展示了 PML NB 在促进 HSV-1 潜伏状态建立方面的主要作用。 HSV-1潜伏期建立的一个标志是包含病毒基因组的PML NB的形成，我们将其称为“包含病毒DNA的PML NB”（vDCP NB）。包埋在 vDCP NB 中的基因组在转录上被沉默。然而，这种自然发生的潜伏/静止状态可以通过转录方式重新激活。因此，了解 PML NB 在控制 HSV-1 潜伏期的建立及其再激活中的作用对于设计基于预防病毒再激活的新治疗方法至关重要。
Herpes simplex virus 1 (HSV-1) latency establishment is tightly controlled by promyelocytic leukemia (PML) nuclear bodies (NBs) (or ND10), although their exact contribution is still elusive. A hallmark of HSV-1 latency is the interaction between latent viral genomes and PML NBs, leading to the formation of viral DNA-containing PML NBs (vDCP NBs), and the complete silencing of HSV-1. Using a replication-defective HSV-1-infected human primary fibroblast model reproducing the formation of vDCP NBs, combined with an immuno-FISH approach developed to detect latent/quiescent HSV-1, we show that vDCP NBs contain both histone H3.3 and its chaperone complexes, i.e., DAXX/ATRX and HIRA complex (HIRA, UBN1, CABIN1, and ASF1a). HIRA also co-localizes with vDCP NBs present in trigeminal ganglia (TG) neurons from HSV-1-infected wild type mice. ChIP and Re-ChIP show that vDCP NBs-associated latent/quiescent viral genomes are chromatinized almost exclusively with H3.3 modified on its lysine (K) 9 by trimethylation, consistent with an interaction of the H3.3 chaperones with multiple viral loci and with the transcriptional silencing of HSV-1. Only simultaneous inactivation of both H3.3 chaperone complexes has a significant impact on the deposition of H3.3 on viral genomes, suggesting a compensation mechanism. In contrast, the sole depletion of PML significantly impacts the chromatinization of the latent/quiescent viral genomes with H3.3 without any overall replacement with H3.1. vDCP NBs-associated HSV-1 genomes are not definitively silenced since the destabilization of vDCP NBs by ICP0, which is essential for HSV-1 reactivation in vivo, allows the recovery of a transcriptional lytic program and the replication of viral genomes. Consequently, the present study demonstrates a specific chromatin regulation of vDCP NBs-associated latent/quiescent HSV-1 through an H3.3-dependent HSV-1 chromatinization involving the two H3.3 chaperones DAXX/ATRX and HIRA complexes. Additionally, the study reveals that PML NBs are major actors in latent/quiescent HSV-1 H3.3 chromatinization through a PML NB/histone H3.3/H3.3 chaperone axis. An understanding of the molecular mechanisms contributing to the persistence of a virus in its host is essential to be able to control viral reactivation and its associated diseases. Herpes simplex virus 1 (HSV-1) is a human pathogen that remains latent in the PNS and CNS of the infected host. The latency is unstable, and frequent reactivations of the virus are responsible for PNS and CNS pathologies. It is thus crucial to understand the physiological, immunological and molecular levels of interplay between latent HSV-1 and the host. Promyelocytic leukemia (PML) nuclear bodies (NBs) control viral infections by preventing the onset of lytic infection. In previous studies, we showed a major role of PML NBs in favoring the establishment of a latent state for HSV-1. A hallmark of HSV-1 latency establishment is the formation of PML NBs containing the viral genome, which we called “viral DNA-containing PML NBs” (vDCP NBs). The genome entrapped in the vDCP NBs is transcriptionally silenced. This naturally occurring latent/quiescent state could, however, be transcriptionally reactivated. Therefore, understanding the role of PML NBs in controlling the establishment of HSV-1 latency and its reactivation is essential to design new therapeutic approaches based on the prevention of viral reactivation.
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影响因子：
10.5
作者：
Drane, Pascal;Ouararhni, Khalid;Hamiche, Ali
通讯作者：
Hamiche, Ali
DOI：
10.4161/cc.26988
发表时间：
2014
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Corpet A;Olbrich T;Gwerder M;Fink D;Stucki M
通讯作者：
Stucki M
影响因子：
5.4
作者：
Doehner, Katinka;Radtke, Kerstin;Sodeik, Beate
通讯作者：
Sodeik, Beate
影响因子：
7
作者：
Delbarre E;Ivanauskiene K;Küntziger T;Collas P
通讯作者：
Collas P
影响因子：
5.3
作者：
Banumathy, Gowrishankar;Somaiah, Neeta;Adams, Peter D.
通讯作者：
Adams, Peter D.