Human cytomegalovirus infection dysregulates the canonical Wnt/β-catenin signaling pathway.
Human cytomegalovirus infection dysregulates the canonical Wnt/β-catenin signaling pathway.
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DOI：
10.1371/journal.ppat.1002959
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Sullivan DE
中科院分区：
文献类型：
--
作者：
Angelova M;Zwezdaryk K;Ferris M;Shan B;Morris CA;Sullivan DE
人巨细胞病毒（HCMV）是一种普遍存在的疱疹病毒，目前感染了世界上很大一部分人口。虽然在健康个体中通常无症状，但怀孕期间的HCMV感染可导致自然流产、早产或子宫内感染的婴儿的永久性神经残疾。在感染过程中，病毒对多种宿主信号通路施加控制。Wnt/β-catenin信号通路是细胞周期调控、分化、胚胎发育、胎盘形成和转移的重要途径，病毒常使其失调。HCMV感染如何影响这一关键途径目前尚不清楚。在这项研究中，我们证明了HCMV在真皮成纤维细胞和人胎盘绒毛外滋养层细胞中的Wnt/β-catenin信号转导失调。感染抑制Wnt诱导的β-连环蛋白的转录活性和这些细胞中β-连环蛋白靶基因的表达。HCMV感染导致β-catenin蛋白在不连续的胞核区域积聚。感染后，膜相关和胞质池中的β-连环蛋白以及核β-连环蛋白水平降低;而β-连环蛋白基因的转录没有变化，表明降解增强。鉴于Wnt/β-连环蛋白信号在细胞过程中的关键作用，这些发现代表了HCMV破坏正常细胞功能的一种新的重要机制。世界人口中有很大比例感染了HCMV。作为发达国家出生缺陷的主要病毒原因，HCMV代表了重大的公共卫生负担。我们首次报道了HCMV感染使经典Wnt/β-catenin信号通路失调，该通路在调节多种生物学功能中是必不可少的。我们证明，HCMV感染导致β-catenin蛋白（通路中的效应转录因子）的隔离和降解，从而阻止其下游信号传导活性。由于该途径在调节哺乳动物发育和体内平衡中是必不可少的，因此HCMV损害该途径的发现对于理解病毒发病机制，特别是与HCMV疾病相关的病毒发病机制变得具有全球重要性。
Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that currently infects a large percentage of the world population. Although usually asymptomatic in healthy individuals, HCMV infection during pregnancy may cause spontaneous abortions, premature delivery, or permanent neurological disabilities in infants infected in utero. During infection, the virus exerts control over a multitude of host signaling pathways. Wnt/β-catenin signaling, an essential pathway involved in cell cycle control, differentiation, embryonic development, placentation and metastasis, is frequently dysregulated by viruses. How HCMV infection affects this critical pathway is not currently known. In this study, we demonstrate that HCMV dysregulates Wnt/β-catenin signaling in dermal fibroblasts and human placental extravillous trophoblasts. Infection inhibits Wnt-induced transcriptional activity of β-catenin and expression of β-catenin target genes in these cells. HCMV infection leads to β-catenin protein accumulation in a discrete juxtanuclear region. Levels of β-catenin in membrane-associated and cytosolic pools, as well as nuclear β-catenin, are reduced after infection; while transcription of the β-catenin gene is unchanged, suggesting enhanced degradation. Given the critical role of Wnt/β-catenin signaling in cellular processes, these findings represent a novel and important mechanism whereby HCMV disrupts normal cellular function. A large percentage of the world population is infected with HCMV. As a leading viral cause of birth defects in the developed world, HCMV represents a significant public health burden. For the first time, we report that HCMV infection dysregulates the canonical Wnt/β-catenin signaling pathway which is essential in regulating a diverse range of biological functions. We demonstrate that HCMV infection leads to sequestration and degradation of β-catenin protein, the effector transcription factor in the pathway, thus preventing its downstream signaling activities. Since this pathway is essential in regulating mammalian development and homeostasis, the finding that HCMV impairs this pathway becomes globally important for understanding viral pathogenesis, particularly that related to HCMV disease.
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DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
影响因子：
3.1
作者：
Ghanevati, M;Miller, CA
通讯作者：
Miller, CA
影响因子：
3.7
作者：
Bresnahan, WA;Boldogh, I;Albrecht, T
通讯作者：
Albrecht, T
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
11.4
作者：
Aberle, H;Bauer, A;Kemler, R
通讯作者：
Kemler, R