JCPyV-Induced MAPK Signaling Activates Transcription Factors during Infection
JCPyV-Induced MAPK Signaling Activates Transcription Factors during Infection
复制标题
DOI：
10.3390/ijms20194779
复制
发表时间：
2019-10-01
影响因子：
5.6
通讯作者：
Maginnis, Melissa S.
中科院分区：
文献类型：
--
作者：
DuShane, Jeanne K.;Mayberry, Colleen L.;Maginnis, Melissa S.
JC多瘤病毒（JCPyV）是一种普遍存在的人类病原体，是致死性神经退行性疾病进行性多灶性白质脑病（PML）的病因。与大多数病毒一样，JCPyV感染需要激活宿主细胞信号通路以促进病毒复制过程。先前的研究已经确定细胞外信号调节激酶（ERK）是促进JCPyV基因组转录的必要性，ERK是丝裂原活化蛋白激酶（MAPK）级联（MAPK-ERK）的末端核心激酶。然而，MAPK-ERK通路被激活并诱导病毒转录的潜在机制尚不清楚。用Raf和MAP激酶激酶（MEK）特异性sirna处理细胞，在MAPK-ERK级联中靶向蛋白，显著减少JCPyV感染。MEK是负责ERK磷酸化的双特异性激酶，其磷酸化有时与病毒感染周期的早期事件一致。此外，MAPK特异性信号阵列显示，MAPK级联下游的转录因子，包括cMyc和SMAD4，在感染细胞中上调。共聚焦显微镜分析表明，cMyc和SMAD4在感染过程中穿梭到细胞核，当ERK受到抑制时，细胞核定位减少。这些发现表明，JCPyV诱导MAPK-ERK通路是由Raf和MEK介导的，并在感染过程中导致下游转录因子的激活。本研究进一步确定了MAPK级联在JCPyV感染过程中的作用及其下游信号转导后果，阐明了激酶是病毒感染的潜在治疗靶点。
JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection.