Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois, USA.
J Virol. 2018 Nov 12;92(23). doi: 10.1128/JVI.01179-18. Print 2018 Dec 1.
Herpes simplex virus 2 (HSV-2) can productively infect many different cell types of human and nonhuman origin. Here we demonstrate interconnected roles for two host enzymes, heparanase (HPSE) and cathepsin L, in HSV-2 release from cells. In vaginal epithelial cells, HSV-2 causes heparan sulfate shedding and upregulation in HPSE levels during the productive phase of infection. We also noted increased levels of cathepsin L and show that regulation of HPSE by cathepsin L via cleavage of HPSE proenzyme is important for infection. Furthermore, inhibition of HPSE by a specific inhibitor, OGT 2115, dramatically reduces HSV-2 release from vaginal epithelial cells. Likewise, we show evidence that the inhibition of cathepsin L is detrimental to the infection. The HPSE increase after infection is mediated by an increased NF-κB nuclear localization and a resultant activation of HPSE transcription. Together these mechanisms contribute to the removal of heparan sulfate from the cell surface and thus facilitate virus release from cells. Genital infections by HSV-2 represent one of the most common sexually transmitted viral infections. The virus causes painful lesions and sores around the genitals or rectum. Intermittent release of the virus from infected tissues during sexual activities is the most common cause of transmission. At the molecular level, cell surface heparan sulfate (HS) is known to provide attachment sites for HSV-2. While the removal of HS during HSV-1 release has been shown, not much is known about the host factors and their regulators that contribute to HSV-2 release from natural target cell types. Here we suggest a role for the host enzyme heparanase in HSV-2 release. Our work reveals that in addition to the regulation of transcription by NF-κB, HPSE is also regulated posttranslationally by cathepsin L and that inhibition of heparanase activity directly affects HSV-2 release. We provide unique insights into the host mechanisms controlling HSV-2 egress and spread.
单纯疱疹病毒 2 (HSV-2) 可以有效地感染人类和非人类来源的许多不同类型的细胞。在这里，我们证明了两种宿主酶，肝素酶 (HPSE) 和组织蛋白酶 L，在 HSV-2 从细胞中释放过程中的相互关联的作用。在阴道上皮细胞中，HSV-2 在感染的产毒阶段导致肝素硫酸的脱落和 HPSE 水平的上调。我们还注意到组织蛋白酶 L 的水平增加，并表明组织蛋白酶 L 通过切割 HPSE 原酶对 HPSE 的调节对于感染很重要。此外，通过特定抑制剂 OGT 2115 抑制 HPSE 会大大减少阴道上皮细胞中 HSV-2 的释放。同样，我们证明了抑制组织蛋白酶 L 不利于感染。感染后 HPSE 的增加是由 NF-κB 核定位增加和 HPSE 转录的激活介导的。这些机制共同促进了细胞表面肝素硫酸的去除，从而促进了病毒从细胞中的释放。HSV-2 引起的生殖器感染是最常见的性传播病毒感染之一。该病毒会导致生殖器或直肠周围出现疼痛的病变和溃疡。在性活动期间，从受感染组织间歇性释放病毒是最常见的传播原因。在分子水平上，已知细胞表面肝素硫酸 (HS) 为 HSV-2 提供附着位点。虽然已经证明了在 HSV-1 释放过程中 HS 的去除，但对于有助于 HSV-2 从天然靶细胞类型中释放的宿主因子及其调节剂知之甚少。在这里，我们提出了宿主酶肝素酶在 HSV-2 释放中的作用。我们的工作表明，除了 NF-κB 对转录的调节外，HPSE 还通过组织蛋白酶 L 进行翻译后调节，并且抑制肝素酶活性直接影响 HSV-2 的释放。我们提供了对控制 HSV-2 逸出和传播的宿主机制的独特见解。
