The human JC polyomavirus (JCPyV) infects the majority of the population worldwide and presents as an asymptomatic, persistent infection in the kidneys. In individuals who are immunocompromised, JCPyV can become reactivated and cause a lytic infection in the central nervous system resulting in the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML). Infection is initiated by interactions between the capsid protein viral protein 1 (VP1) and the α2,6-linked sialic acid on lactoseries tetrasaccharide c (LSTc), while JCPyV internalization is facilitated by 5-hydroxytryptamine 2 receptors (5-HT₂Rs). The mechanisms by which the serotonin receptors mediate virus entry and the signaling cascades required to drive viral infection remain poorly understood. JCPyV was previously shown to induce phosphorylation of extracellular signal-regulated kinase (ERK), a downstream target of the mitogen-activated protein kinase (MAPK) pathway, upon virus entry. However, it remained unclear whether ERK activation was required for JCPyV infection. Both ERK-specific small interfering RNA (siRNA) and ERK inhibitor treatments resulted in significantly diminished JCPyV infection in both kidney and glial cells yet had no effect on the infectivity of the polyomavirus simian virus 40 (SV40). Experiments characterizing the role of ERK during steps in the viral life cycle indicate that ERK activation is required for viral transcription, as demonstrated by a significant reduction in production of large T antigen (TAg), a key viral protein associated with the initiation of viral transcription and viral replication. These findings delineate the role of the MAPK-ERK signaling pathway in JCPyV infection, elucidating how the virus reprograms the host cell to promote viral pathogenesis.

IMPORTANCE Viral infection is dependent upon host cell factors, including the activation of cellular signaling pathways. These interactions between viruses and host cells are necessary for infection and play an important role in viral disease outcomes. The focus of this study was to determine how the human JC polyomavirus (JCPyV), a virus that resides in the kidney of the majority of the population and can cause the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brains of immunosuppressed individuals, usurps a cellular signaling pathway to promote its own infectious life cycle. We demonstrated that the activation of extracellular signal-regulated kinase (ERK), a component of the mitogen-activated protein kinase (MAPK) pathway, promotes JCPyV transcription, which is required for viral infection. Our findings demonstrate that the MAPK-ERK signaling pathway is a key determinant of JCPyV infection, elucidating new information regarding the signal reprogramming of host cells by a pathogenic virus.

人类JC多瘤病毒（JCPyV）感染世界各地的大多数人口，并表现为肾脏的无症状，持续性感染。在免疫功能低下的个体中，JCPyV可以重新激活并引起中枢神经系统的溶菌性感染，从而导致致命的脱髓鞘疾病进行性多灶性白质脑病（PML）。感染是由衣壳蛋白病毒蛋白1（VP1）和乳酸系列四糖c（LSTc）上的α2,6-连接的唾液酸之间的相互作用引发的，而JCPyV的内在化是由5-羟色胺2受体（5-HT ₂Rs）。血清素受体介导病毒进入的机制和驱动病毒感染所需的信号传导级联仍然知之甚少。先前显示，JCPyV会在病毒进入时诱导细胞外信号调节激酶（ERK）的磷酸化，ERK是有丝分裂原激活的蛋白激酶（MAPK）途径的下游目标。但是，尚不清楚JCPyV感染是否需要激活ERK。ERK特异性小干扰RNA（siRNA）和ERK抑制剂治疗均导致肾脏和神经胶质细胞JCPyV感染显着减少，但对多瘤病毒猿猴病毒40（SV40）的感染性没有影响。表征ERK在病毒生命周期各个步骤中的作用的实验表明，ERK激活是病毒转录所必需的，如大量T抗原（TAg）的产生显着减少所证明的，TAg是与病毒转录和病毒复制的启动相关的关键病毒蛋白。这些发现描述了MAPK-ERK信号通路在JCPyV感染中的作用，阐明了病毒如何重编程宿主细胞以促进病毒发病机理。

重要性病毒感染取决于宿主细胞因素，包括细胞信号通路的激活。病毒和宿主细胞之间的这些相互作用是感染所必需的，并且在病毒性疾病的预后中起着重要的作用。这项研究的重点是确定人类JC多瘤病毒（JCPyV）是一种驻留在大多数人群肾脏中的病毒，如何在免疫抑制个体的大脑中引起致命的脱髓鞘疾病进行性多灶性白质脑病（PML）干扰细胞信号通路来促进其自身的感染生命周期。我们证明，细胞外信号调节激酶（ERK）的激活是有丝分裂原激活的蛋白激酶（MAPK）途径的组成部分，可促进病毒感染所需的JCPyV转录。