Respiratory syncytial virus decreases p53 protein to prolong survival of airway epithelial cells.
Respiratory syncytial virus (RSV) is a clinically important pathogen. It preferentially infects airway epithelial cells causing bronchiolitis in infants, exacerbations in patients with obstructive lung disease, and life-threatening pneumonia in the immunosuppressed. The p53 protein is a tumor suppressor protein that promotes apoptosis and is tightly regulated for optimal cell growth and survival. A critical negative regulator of p53 is murine double minute 2 (Mdm2), an E3 ubiquitin ligase that targets p53 for proteasome degradation. Mdm2 is activated by phospho-Akt, and we previously showed that RSV activates Akt and delays apoptosis in primary human airway epithelial cells. In this study, we explore further the mechanism by which RSV regulates p53 to delay apoptosis but paradoxically enhance inflammation. We found that RSV activates Mdm2 1-6 h after infection resulting in a decrease in p53 6-24 h after infection. The p53 down-regulation correlates with increased airway epithelial cell longevity. Importantly, inhibition of the PI3K/Akt pathway blocks the activation of Mdm2 by RSV and preserves the p53 response. The effects of RSV infection are antagonized by Nutlin-3, a specific chemical inhibitor that prevents the Mdm2/p53 association. Nutlin-3 treatment increases endogenous p53 expression in RSV infected cells, causing earlier cell death. This same increase in p53 enhances viral replication and limits the inflammatory response as measured by IL-6 protein. These findings reveal that RSV decreases p53 by enhancing Akt/Mdm2-mediated p53 degradation, thereby delaying apoptosis and prolonging survival of airway epithelial cells.
Groskreutz
Dayna J
DJ
Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Pharmacology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA. Dayna-Groskreutz@uiowa.edu
Monick
Martha M
MM
Yarovinsky
Timur O
TO
Powers
Linda S
LS
Quelle
Dawn E
DE
Varga
Steven M
SM
Look
Dwight C
DC
Hunninghake
Gary W
GW
D017209:Apoptosis; D002470:Cell Survival; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012136:Respiratory Syncytial Viruses / Q000502:physiology*; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication; D000093242:Interleukin-6 Inhibitors
D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; D000093242:Interleukin-6 Inhibitors; C482205:nutlin 3