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

Significance Statement

Measles virus (MeV) is one of the most important pathogens in humans, and causes several unique syndromes including transient immunosuppression. To clarify the cellular responses to measles virus infection, we previously analyzed a measles virus-infected epithelial cell line and a lymphoid cell line by microarray, and showed that a characteristic comprehensive downregulation of housekeeping genes is induced during late stage infection. By examining this phenomenon, we revealed that the continuous dephosphorylation of DNA-PKcs by its associated PP5 induces the constitutive phosphorylation of Sp1 and the maintenance of c-Myc protein levels, both of which are crucial for the comprehensive expression of housekeeping genes in cells under nonstimulated steady-state conditions. We also showed that the accumulation of viral nucleocapsid triggered PP5 inactivation, reduced Sp1 activity, and caused the degradation of c-Myc. These findings uncover a novel strategy of measles virus during infection, which causes the collapse of host cellular functions.

About The Author

Prof. Chieko Kai received her Ph.D in Veterinary Medical Science, The University of Tokyo in 1983. After that, she got a position of an Assistant Professor in Institute of Medical Science, The University of Tokyo, worked as a visiting fellow in Department of Tumor Biology, Karolinska Institute, Sweden between 1985-1987, and then obtained a position as an Associate Professor at Department of Veterinary Microbiology, Graduate School of Agriculture. In November 1999, she was appointed to the full professorship in Institute of Medical Science, The University of Tokyo.  She has also a professor position in the international Research Center for Infectious Diseases in Institute as well since 2005 till now, and also the Director of Laboratory Animal Research Center since Apr 2000. She was the Vice-Dean of the Institute from 2003 to 2004.  She is a member of Science Council of Japan. Her major research interests are to elucidate molecular mechanisms of pathogenicity and species specificity of negative and single strand RNA viruses (Mononegavirales), and to control viral diseases. For these purposes, her group is studying virus replication and identifying viral and host factors important for the expression of pathogenicity using a novel reverse genetics technique. Her group is also developing new virus vaccines to infectious diseases, and a novel cancer therapy using oncolytic viruses by genetic engineering.

Dr. Hiroki Sato received his PhD from Chiba University in 1999, and joined Dr. Chieko Kai’s lab; Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo. He is an assistant professor and his current research focuses on the mechanisms of cell-type specific cellular responses and comprehensive network of post transcriptional modifications after morbillivirus infection.

Photo shows professor Kai (right) and Dr. Sato (left)

Figure Legend:  The intracellular accumulation of viral nucleocapsid causes the inactivation of PP5, autophosphorylation and the resulting inactivation of DNA-PKcs, then the downstream reduction of Sp1 phosphorylation and degradation of c-Myc, both of which cause their inactivation and consequent downregulation of housekeeping genes.

 

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

Journal Reference

J Virol. 2015 Oct;89(19):9709-18.

Sato H1, Yoneda M1, Honma R2, Ikeda F1, Watanabe S2, Kai C3.

Show Affiliations
  1. Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  2. Clinical Informatics, Tokyo Medical and Dental University, Tokyo, Japan.
  3. Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan [email protected]

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. Measles virus 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 Measles virus 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 Measles virus 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 Measles virus.

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