Focusing in on herpesvirus The herpesvirus family includes herpes simplex virus type 1 (HSV-1), which causes cold sores, and type 2 (HSV-2), which causes genital herpes. Herpesviruses comprise a large DNA genome enclosed in a large and complex protein cage called a capsid (see the Perspective by Heldwein). Dai and Zhou used electron microscopy to determine a high-resolution structure of the HSV-1 capsid bound to the tegument proteins that occupy the space between the capsid and the nuclear envelope. The structure suggests how these components may play a role in viral transport. Yuan et al. describe a higher-resolution structure of an HSV-2 capsid, providing insight into how the shell assembles and is stabilized. Science, this issue p. eaao7298, p. eaao7283; see also p. 34 Electron microscopy structures provide insight into the function of the herpesviruses that cause cold sores and genital herpes. INTRODUCTION Since Hippocrates first described the cutaneous spreading of herpes simplex lesions, many other diseases—chickenpox, infectious mononucleosis, nasopharyngeal carcinoma, and Kaposi’s sarcoma—have been found to be associated with the nine known human herpesviruses. Among them, herpes simplex virus type 1 (HSV-1, causes cold sores), type 2 (HSV-2, causes genital herpes), and varicella-zoster virus (causes chickenpox and shingles)—which all belong to the α-herpesvirus subfamily—can establish lifelong latent infection within our peripheral nervous system. RATIONALE A prominent feature of these neurotropic viruses is the long-range (up to tens of centimeters) axonal retrograde transport of the DNA-containing viral capsid from nerve endings at sites of infection (such as the lips) to neuronal cell bodies at the ganglia to establish latency or, upon reactivation, anterograde transport of the progeny viral particles from the ganglia to nerve terminals, resulting in reinfection of the dermis. Capsid-associated tegument complexes (CATCs) have been demonstrated to be involved in this cytoskeleton-dependent capsid transport. Because of the large size (~1300 Å) of HSV-1 particles, it has been difficult to obtain atomic structures of the HSV-1 capsid and CATC; consequently, the structural bases underlying α-herpesviruses’ remarkable capability of long-range neuronal transport and many other aspects of its life cycle are poorly understood. RESULTS By using cryo–electron microscopy, we obtained an atomic model of the HSV-1 capsid with CATC, comprising multiple conformers of the capsid proteins VP5, VP19c, VP23, and VP26 and tegument proteins pUL17, pUL25, and pUL36. Crowning every capsid vertex are five copies of heteropentameric CATC. The pUL17 monomer in each CATC bridges over triplexes Ta and Tc on the capsid surface and supports a coiled-coil helix bundle of a pUL25 dimer and a pUL36 dimer, thus positioning their flexible domains for potential involvement in nuclear egress and axonal transport of the capsid. The single C-terminal helix of pUL36 resolved in the CATC links the capsid to the outer tegument and envelope: As the largest tegument protein in all herpesviruses and essential for virion formation, pUL36 has been shown to interact extensively with other tegument proteins, which in turn interact with envelope glycoproteins. Architectural similarities between herpesvirus triplex proteins and auxiliary cementing protein gpD in bacteriophage λ, in addition to the bacteriophage HK97 gp5–like folds in their major capsid proteins and structural similarities in their DNA packaging and delivery apparatuses, indicate that the commonality between bacteriophages and herpesviruses extends to their auxiliary components. Notwithstanding this broad evolutionary conservation, comparison of HSV-1 capsid proteins with those of other herpesviruses revealed extraordinary structural diversities in the forms of domain insertion and conformation polymorphism, not only for tegument interactions but also for DNA encapsulation. CONCLUSION Our structure of the HSV-1 capsid with capsid-associated tegument proteins provides mechanistic insights into multiple aspects of the viral life cycle, including capsid assembly, nuclear egress, acquisition of tegument and envelope, and axonal transport in neuronal cells. The numerous molecular interactions and atomic details embodied in the structure make it a much-sought-after atlas for the search of antivirals targeting these critical steps of HSV-1 lytic replication. Structure of the HSV-1 capsid with capsid-associated tegument proteins. Surface view of a 4.2-Å resolution map of the icosahedral capsid, with a single facet shown in color. The structure of the vertex region (magnified view) was improved to 3.5-Å resolution by subparticle refinement. P, peripentonal; C, center; E, edge; Ta to Te, heterotrimeric triplexes composed of Tri1, Tri2A, and Tri2B. Herpes simplex viruses (HSVs) rely on capsid-associated tegument complex (CATC) for long-range axonal transport of their genome-containing capsids between sites of infection and neuronal cell bodies. Here we report cryo–electron microscopy structures of the HSV-1 capsid with CATC up to 3.5-angstrom resolution and atomic models of multiple conformers of capsid proteins VP5, VP19c, VP23, and VP26 and tegument proteins pUL17, pUL25, and pUL36. Crowning every capsid vertex are five copies of heteropentameric CATC, each containing a pUL17 monomer supporting the coiled-coil helix bundle of a pUL25 dimer and a pUL36 dimer, thus positioning their flexible domains for potential involvement in nuclear capsid egress and axonal capsid transport. Notwithstanding newly discovered fold conservation between triplex proteins and bacteriophage λ protein gpD and the previously recognized bacteriophage HK97 gp5–like fold in VP5, HSV-1 capsid proteins exhibit extraordinary diversity in forms of domain insertion and conformational polymorphism, not only for interactions with tegument proteins but also for encapsulation of large genomes.

中文翻译：

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单纯疱疹病毒 1 衣壳与相关外皮蛋白复合物的结构

关注疱疹病毒 疱疹病毒家族包括引起唇疱疹的单纯疱疹病毒 1 型 (HSV-1) 和引起生殖器疱疹的 2 型 (HSV-2)。疱疹病毒包含一个大型 DNA 基因组，该基因组包含在称为衣壳的大型复杂蛋白质笼中（参见 Heldwein 的观点）。Dai 和 Zhou 使用电子显微镜来确定 HSV-1 衣壳与占据衣壳和核膜之间空间的外皮蛋白结合的高分辨率结构。该结构表明这些成分如何在病毒运输中发挥作用。袁等人。描述了 HSV-2 衣壳的更高分辨率结构，提供了对壳如何组装和稳定的深入了解。科学，这个问题 p。eaao7298，第。eaao7283; 另见第。34 电子显微镜结构有助于深入了解导致唇疱疹和生殖器疱疹的疱疹病毒的功能。引言 自从希波克拉底首次描述了单纯疱疹病灶的皮肤扩散后，许多其他疾病——水痘、传染性单核细胞增多症、鼻咽癌和卡波西肉瘤——已被发现与九种已知的人类疱疹病毒有关。其中，单纯疱疹病毒1型（HSV-1，引起唇疱疹）、2型（HSV-2，引起生殖器疱疹）和水痘-带状疱疹病毒（引起水痘和带状疱疹）——都属于α-疱疹病毒亚科——可以在我们的周围神经系统内建立终生的潜伏感染。基本原理这些嗜神经病毒的一个显着特征是含有 DNA 的病毒衣壳从感染部位（如嘴唇）的神经末梢到神经节的神经元细胞体的长距离（高达数十厘米）轴突逆行运输建立潜伏期，或在重新激活后，将子代病毒颗粒从神经节顺行运输到神经末梢，导致真皮再次感染。衣壳相关的被膜复合物 (CATC) 已被证明参与了这种依赖于细胞骨架的衣壳运输。由于 HSV-1 颗粒尺寸较大（~1300 Å），很难获得 HSV-1 衣壳和 CATC 的原子结构；最后，α-疱疹病毒具有非凡的远距离神经元运输能力及其生命周期的许多其他方面的结构基础知之甚少。结果通过使用冷冻电子显微镜，我们获得了带有 CATC 的 HSV-1 衣壳的原子模型，包括衣壳蛋白 VP5、VP19c、VP23 和 VP26 的多个构象异构体以及被皮蛋白 pUL17、pUL25 和 pUL36。加冕每个衣壳顶点是异五聚体 CATC 的五个副本。每个 CATC 中的 pUL17 单体在衣壳表面的三链体 Ta 和 Tc 上桥接，并支持 pUL25 二聚体和 pUL36 二聚体的卷曲螺旋束，从而定位它们的灵活结构域，以可能参与衣壳的核出口和轴突运输. 在 CATC 中解析的 pUL36 的单个 C 端螺旋将衣壳连接到外皮和包膜：作为所有疱疹病毒中最大的外皮蛋白并且对病毒体形成必不可少，pUL36 已被证明与其他外皮蛋白广泛相互作用，在转而与包膜糖蛋白相互作用。除了噬菌体 λ 中的噬菌体 HK97 gp5 样折叠以及它们的 DNA 包装和递送装置的结构相似性之外，噬菌体 λ 中疱疹病毒三链体蛋白和辅助胶结蛋白 gpD 之间的结构相似性表明噬菌体和疱疹病毒之间的共性扩展了到他们的辅助组件。尽管有这种广泛的进化保护，HSV-1 衣壳蛋白与其他疱疹病毒的衣壳蛋白的比较揭示了结构域插入和构象多态性形式的非凡结构多样性，不仅对于外皮相互作用，而且对于 DNA 封装。结论我们的 HSV-1 衣壳与衣壳相关的外被蛋白的结构提供了对病毒生命周期多个方面的机械见解，包括衣壳组装、核出口、外皮和包膜的获得以及神经元细胞中的轴突运输。结构中包含的众多分子相互作用和原子细节使其成为寻找针对 HSV-1 裂解复制的这些关键步骤的抗病毒药物的广受欢迎的图谱。HSV-1 衣壳与衣壳相关外皮蛋白的结构。4. 表面视图 二十面体衣壳的 2 Å 分辨率图，单面以彩色显示。通过亚粒子细化，顶点区域的结构（放大视图）提高到 3.5 Å 分辨率。P，peripentonal; C、中心；E、边缘；Ta 到 Te，由 Tri1、Tri2A 和 Tri2B 组成的异三聚体三链体。单纯疱疹病毒 (HSV) 依靠衣壳相关被膜复合物 (CATC) 在感染部位和神经元细胞体之间进行含有基因组的衣壳的长距离轴突运输。在这里，我们报告了具有高达 3.5 埃分辨率的 CATC 的 HSV-1 衣壳的冷冻电子显微镜结构以及衣壳蛋白 VP5、VP19c、VP23 和 VP26 以及被膜蛋白 pUL17、pUL25 和 pUL36 的多个构象异构体的原子模型。加冕每个衣壳顶点是异五聚体 CATC 的五个副本，每个都包含 pUL17 单体，支持 pUL25 二聚体和 pUL36 二聚体的卷曲螺旋螺旋束，从而将它们的灵活结构域定位为可能参与核衣壳出口和轴突衣壳运输。尽管新发现三链体蛋白和噬菌体 λ 蛋白 gpD 和先前公认的噬菌体 HK97 gp5 在 VP5 中的折叠保守性，HSV-1 衣壳蛋白在结构域插入和构象多态性方面表现出非凡的多样性，不仅是与被皮蛋白的相互作用也用于封装大基因组。