Measles Virus Infection Inactivates Cellular Protein Phosphatase 5 with Consequent Suppression of Sp1 and c-Myc Activities

Abstract

Measles virus (MeV) causes several unique syndromes, including transient immunosuppression. To clarify the cellular responses to MeV infection, we previously analyzed a MeV-infected epithelial cell line and a lymphoid cell line by microarray and showed that the expression of numerous genes was up-or downregulated in the epithelial cells. In particular, there was a characteristic comprehensive downregulation of housekeeping genes during late stage infection. To identify the mechanism underlying this phenomenon, we examined the phosphorylation status of transcription factors and kinase/phosphatase activities in epithelial cells after infection. MeV infection inactivated cellular protein phosphatase 5 (PP5) that consequently inactivated DNA-dependent protein kinase, which reduced Sp1 phosphorylation levels, and c-Myc degradation, both of which downregulated the expression of many housekeeping genes. In addition, intracellular accumulation of viral nucleocapsid inactivated PP5 and subsequent downstream responses. These findings demonstrate a novel strategy of MeV during infection, which causes the collapse of host cellular functions. IMPORTANCE Measles virus (MeV) is one of the most important pathogens in humans. We previously showed that MeV infection induces the comprehensive downregulation of housekeeping genes in epithelial cells. By examining this phenomenon, we clarified the molecular mechanism underlying the constitutive expression of housekeeping genes in cells, which is maintained by cellular protein phosphatase 5 (PP5) and DNA-dependent protein kinase. We also demonstrated that MeV targets PP5 for downregulation in epithelial cells. This is the first report to show how MeV infection triggers a reduction in overall cellular functions of infected host cells. Our findings will help uncover unique pathogenicities caused by MeV.M easles virus (MeV) is one of the most important pathogens in humans and is a major cause of child mortality, particularly in developing countries (1). Therefore, MeV has been targeted for eradication by the World Health Organization. MeV infection causes several characteristic syndromes, including transient immunosuppression (1). MeV infection induces different immune responses in epithelial and lymphoid cells in vitro. For example, MeV infection induces the rapid activation of antiviral factors (2-4) and consequent production of various cytokines (3, 5, 6) in epithelial cells. In contrast, these cellular responses are suppressed in MeV-infected lymphoid cells (7-9).To clarify the cell-type-specific responses to wild-type MeV infection, we previously performed a microarray analysis using two different cell types (10). Experiments were designed to assess the time course of gene expression patterns in human epithelial cells (HEK293 cell line that stably expresses the receptor SLAM; 293SLAM cells) and lymphoid cells (COBL-a cells), which are the cell types targeted by MeV during primary infection. Many genes were upregulated rapidly in 293SLAM cells, including genes involved in an...

Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase

“…Our previous study demonstrated that MeV induces characteristic comprehensive downregulation of housekeeping genes in epithelial cells [ 13 , 14 ] (Data set: [ 15 ]). We first assigned each downregulated gene to a cellular component group.…”

“…Furthermore, our previous study using microarray analysis revealed that many genes, including antiviral factors, are upregulated [ 13 ]. Interestingly, downregulation of numerous genes, especially housekeeping genes, has also detected during the late stage of infection [ 14 ].…”

Oncolytic Activity of Canine Distemper Virus in Human Ductal Breast Carcinoma Cells

“…Consistently, in our study we also found down-regulation of SP1 in CDV-infected MCF-7 cell line, indicating the role of CDV in silencing of SP1 protein and thus abolishing the activity of proliferation and progression of ductal breast tumor cells. Additionally, Measles virus (member of Pyromixiviridae family) is also reported to be down-regulating the activity of SP1 [27]. On the contrary, SP1 was found to be up-regulated in human cytomegalovirus infection indicating the differential effect on SP1 by different families of virus [28].…”