Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
PLoS Pathog. 2011 Feb 3;7(2):e1001266. doi: 10.1371/journal.ppat.1001266.
The herpesviruses, like most other DNA viruses, replicate in the host cell nucleus. Subnuclear domains known as promyelocytic leukemia protein nuclear bodies (PML-NBs), or ND10 bodies, have been implicated in restricting early herpesviral gene expression. These viruses have evolved countermeasures to disperse PML-NBs, as shown in cells infected in vitro, but information about the fate of PML-NBs and their functions in herpesvirus infected cells in vivo is limited. Varicella-zoster virus (VZV) is an alphaherpesvirus with tropism for skin, lymphocytes and sensory ganglia, where it establishes latency. Here, we identify large PML-NBs that sequester newly assembled nucleocapsids (NC) in neurons and satellite cells of human dorsal root ganglia (DRG) and skin cells infected with VZV in vivo. Quantitative immuno-electron microscopy revealed that these distinctive nuclear bodies consisted of PML fibers forming spherical cages that enclosed mature and immature VZV NCs. Of six PML isoforms, only PML IV promoted the sequestration of NCs. PML IV significantly inhibited viral infection and interacted with the ORF23 capsid surface protein, which was identified as a target for PML-mediated NC sequestration. The unique PML IV C-terminal domain was required for both capsid entrapment and antiviral activity. Similar large PML-NBs, termed clastosomes, sequester aberrant polyglutamine (polyQ) proteins, such as Huntingtin (Htt), in several neurodegenerative disorders. We found that PML IV cages co-sequester HttQ72 and ORF23 protein in VZV infected cells. Our data show that PML cages contribute to the intrinsic antiviral defense by sensing and entrapping VZV nucleocapsids, thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The efficient sequestration of virion capsids in PML cages appears to be the outcome of a basic cytoprotective function of this distinctive category of PML-NBs in sensing and safely containing nuclear aggregates of aberrant proteins.
疱疹病毒与大多数其他 DNA 病毒一样，在宿主细胞核内复制。亚核结构域，称为早幼粒细胞白血病蛋白核体（PML-NBs）或 ND10 体，已被认为可以限制早期疱疹病毒基因的表达。这些病毒已经进化出了分散 PML-NBs 的对策，如在体外感染的细胞中所显示的，但关于 PML-NBs 的命运及其在体内感染疱疹病毒的细胞中的功能的信息是有限的。水痘带状疱疹病毒（VZV）是一种α疱疹病毒，具有皮肤、淋巴细胞和感觉神经节的嗜性，在那里它建立潜伏。在这里，我们在体内感染 VZV 的人背根神经节（DRG）和皮肤细胞的神经元和卫星细胞中鉴定出大型 PML-NBs，这些 PML-NBs 隔离新组装的核衣壳（NC）。定量免疫电子显微镜显示，这些独特的核体由形成球形笼的 PML 纤维组成，这些笼包含成熟和不成熟的 VZV NC。在六种 PML 同工型中，只有 PML IV 促进 NC 的隔离。PML IV 显著抑制病毒感染，并与 ORF23 衣壳表面蛋白相互作用，该蛋白被鉴定为 PML 介导的 NC 隔离的靶标。独特的 PML IV C 末端结构域是外壳捕获和抗病毒活性所必需的。类似的大型 PML-NBs，称为 clastosomes，隔离异常多聚谷氨酰胺（polyQ）蛋白，如 Huntingtin（Htt），在几种神经退行性疾病中。我们发现 PML IV 笼在 VZV 感染的细胞中共同隔离异常的 polyQ72 和 ORF23 蛋白。我们的数据表明，PML 笼通过感知和捕获 VZV 核衣壳来促进固有抗病毒防御，从而阻止它们的核输出并抑制感染性病毒颗粒的形成。病毒衣壳在 PML 笼中的有效隔离似乎是这种独特的 PML-NB 类别在感知和安全容纳异常蛋白质的核聚集体方面的基本细胞保护功能的结果。
