Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.
Suzhou Institute of Systems Medicine, Suzhou, 215123, China.
Curr Top Microbiol Immunol. 2023;442:85-103. doi: 10.1007/82_2020_196.
Herpes simplex virus (HSV)-1 and HSV-2 are ubiquitous human pathogens that infect keratinized epithelial surfaces and establish lifelong latent infection in sensory neurons of the peripheral nervous system. HSV-1 causes oral cold sores, and HSV-2 causes genital lesions characterized by recurrence at the site of the initial infection. In multicellular organisms, cell death plays a pivotal role in host defense by eliminating pathogen-infected cells. Apoptosis and necrosis are readily distinguished types of cell death. Apoptosis, the main form of programmed cell death, depends on the activity of certain caspases, a family of cysteine proteases. Necroptosis, a regulated form of necrosis that is unleashed when caspase activity is compromised, requires the activation of receptor-interacting protein (RIP) kinase 3 (RIPK3) through its interaction with other RIP homotypic interaction motif (RHIM)-containing proteins such as RIPK1. To ensure lifelong infection in the host, HSV carries out sophisticated molecular strategies to evade host cell death responses during viral infection. HSV-1 is a well-characterized pathogen that encodes potent viral inhibitors that modulate both caspase activation in the apoptosis pathway and RIPK3 activation in the necroptosis pathway in a dramatic, species-specific fashion. The viral UL39-encoded viral protein ICP6, the large subunit of the virus-encoded ribonucleotide reductase, functions as a suppressor of both caspase-8 and RHIM-dependent RIPK3 activities in the natural human host. In contrast, ICP6 RHIM-mediated recruitment of RIPK3 in the nonnatural mouse host drives the direct activation of necroptosis. This chapter provides an overview of the current state of the knowledge on molecular interactions between HSV-1 viral proteins and host cell death pathways and highlights how HSV-1 manipulates cell death signals for the benefit of viral propagation.
单纯疱疹病毒 (HSV)-1 和 HSV-2 是普遍存在的人类病原体，它们感染角化上皮表面，并在外周神经系统的感觉神经元中建立终身潜伏感染。HSV-1 引起口腔疱疹，HSV-2 引起生殖器病变，其特征是在初次感染部位复发。在多细胞生物中，细胞死亡通过消除受病原体感染的细胞在宿主防御中起着关键作用。凋亡和坏死是两种易于区分的细胞死亡形式。凋亡，即程序性细胞死亡的主要形式，取决于某些半胱氨酸蛋白酶家族 caspase 的活性。坏死性凋亡是一种受调控的坏死形式，当 caspase 活性受到损害时就会被释放出来，需要通过其与其他包含同源相互作用基序 (RHIM) 的 RIP 蛋白相互作用来激活受体相互作用蛋白 (RIP) 激酶 3 (RIPK3)，例如 RIPK1。为了确保在宿主中长期感染，HSV 在病毒感染过程中会实施复杂的分子策略来逃避宿主细胞死亡反应。HSV-1 是一种特征明确的病原体，它编码有效的病毒抑制剂，以戏剧性的、物种特异性的方式调节凋亡途径中的 caspase 激活和坏死性凋亡途径中的 RIPK3 激活。病毒 UL39 编码的病毒蛋白 ICP6，即病毒编码的核糖核苷酸还原酶的大亚基，作为天然人类宿主中 caspase-8 和 RHIM 依赖性 RIPK3 活性的抑制剂。相比之下，在非天然的小鼠宿主中，ICP6 RHIM 介导的 RIPK3 募集驱动了坏死性凋亡的直接激活。本章概述了 HSV-1 病毒蛋白与宿主细胞死亡途径之间的分子相互作用的最新知识，并强调了 HSV-1 如何操纵细胞死亡信号以促进病毒的传播。
