Department of Ophthalmology and Visual Sciences, University of Illinois at Chicagogrid.185648.6, Chicago, Illinois, USA.
Department of Microbiology and Immunology, University of Illinois at Chicagogrid.185648.6, Chicago, Illinois, USA.
mBio. 2021 Dec 21;12(6):e0279221. doi: 10.1128/mBio.02792-21. Epub 2021 Nov 9.
Under pathological conditions like herpes simplex virus 1 (HSV-1) infection, host-pathogen interactions lead to major reconstruction of the host protein network, which contributes to the dysregulation of signaling pathways and disease onset. Of note is the upregulation of a multifunctional host protein, heparanase (HPSE), following infection, which serves as a mediator in HSV-1 replication. In this study, we identify a novel function of HPSE and highlight it as a key regulator of β-catenin signal transduction. The regulatory role of HPSE on the activation, nuclear translocation, and signal transduction of β-catenin disrupts cellular homeostasis and establishes a pathogenic environment that promotes viral replication. Under normal physiological conditions, β-catenin is bound to a group of proteins, referred to as the destruction complex, and targeted for ubiquitination and, ultimately, degradation. We show that virus-induced upregulation of HPSE leads to the activation of Akt and subsequent stabilization and activation of β-catenin through (i) the release of β-catenin from the destruction complex, and (ii) direct phosphorylation of β-catenin at Ser552. This study also provides an in-depth characterization of the proviral role of β-catenin signaling during HSV-1 replication using physiologically relevant cell lines and models of ocular infection. Furthermore, pharmacological inhibitors of this pathway generated a robust antiviral state against multiple laboratory and clinical strains of HSV-1. Collectively, our findings assign a novel regulatory role to HPSE as a driver of β-catenin signaling in HSV-1 infection. Heparanase (HPSE) and β-catenin have independently been implicated in regulating key pathophysiological processes, including neovascularization, angiogenesis, and inflammation; however, the relationship between the two proteins has remained elusive thus far. For that reason, characterizing this relationship is crucial and can lead to the development of novel therapeutics. For HSV-1 specifically, current antivirals are not able to abolish the virus from the host, leaving patients susceptible to episodes of viral reactivation. Identifying a host-based intervention can provide a better alternative with enhanced efficacy and sustained relief.
在单纯疱疹病毒 1 (HSV-1) 感染等病理条件下，宿主-病原体相互作用导致宿主蛋白网络的主要重构，这有助于信号通路的失调和疾病的发生。值得注意的是，感染后多功能宿主蛋白硫酸乙酰肝素酶 (HPSE) 的上调，它作为 HSV-1 复制的介质。在这项研究中，我们确定了 HPSE 的一个新功能，并强调它是 β-连环蛋白信号转导的关键调节剂。HPSE 对 β-连环蛋白激活、核易位和信号转导的调节作用破坏了细胞内稳态，并建立了促进病毒复制的致病环境。在正常生理条件下，β-连环蛋白与一组称为破坏复合物的蛋白质结合，并被泛素化，最终降解。我们表明，病毒诱导的 HPSE 上调导致 Akt 的激活，随后通过 (i) 破坏复合物中 β-连环蛋白的释放，和 (ii) β-连环蛋白在 Ser552 上的直接磷酸化，导致 β-连环蛋白的稳定和激活。这项研究还使用生理相关的细胞系和眼部感染模型，深入描述了 HSV-1 复制过程中 β-连环蛋白信号的促病毒作用。此外，该途径的药理学抑制剂对多种实验室和临床 HSV-1 株产生了强大的抗病毒状态。总之，我们的研究结果赋予 HPSE 在 HSV-1 感染中作为 β-连环蛋白信号驱动因素的新的调节作用。硫酸乙酰肝素酶 (HPSE) 和 β-连环蛋白都独立地被认为参与调节关键的病理生理过程，包括新生血管形成、血管生成和炎症；然而，这两种蛋白质之间的关系至今仍不清楚。因此，表征这种关系至关重要，并且可以导致新的治疗方法的发展。对于 HSV-1 来说，目前的抗病毒药物并不能将病毒从宿主中清除，使患者容易受到病毒再激活的影响。确定一种基于宿主的干预措施可以提供一种更好的替代方案，具有增强的疗效和持续的缓解作用。
