Kaposi's Sarcoma-Associated Herpesvirus Suppression of DUSP1 Facilitates Cellular Pathogenesis following De Novo Infection
| Autor: | Victoria J. Findlay, Keith L. Kirkwood, Michael Defee, Chris Parsons, Lu Dai, Bryan P. Toole, Dennis K. Watson, Zhiqiang Qin, Jennifer E. Cameron, Francesca Peruzzi |
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| Rok vydání: | 2013 |
| Předmět: |
MAPK/ERK pathway
Immunology Cell Down-Regulation Biology medicine.disease_cause Microbiology Cell Line Downregulation and upregulation Virology medicine Humans Kaposi's sarcoma-associated herpesvirus Regulation of gene expression Kinase Effector Gene Expression Profiling Dual Specificity Phosphatase 1 Cell biology MicroRNAs medicine.anatomical_structure Gene Expression Regulation Insect Science Herpesvirus 8 Human Host-Pathogen Interactions RNA Viral Pathogenesis and Immunity Signal transduction |
| Zdroj: | Journal of Virology. 87:621-635 |
| ISSN: | 1098-5514 0022-538X |
| Popis: | Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), and KSHV activation of mitogen-activated protein kinases (MAPKs) initiates a number of key pathogenic determinants of KS. Direct inhibition of signal transduction as a therapeutic approach presents several challenges, and a better understanding of KSHV-induced mechanisms regulating MAPK activation may facilitate the development of new treatment or prevention strategies for KS. MAPK phosphatases, including dual-specificity phosphatase-1 (DUSP1), negatively regulate signal transduction and cytokine activation through MAPK dephosphorylation or interference with effector molecule binding to MAPKs, including the extracellular signal-regulated kinase (ERK). We found that ERK-dependent latent viral gene expression, the induction of promigratory factors, and cell invasiveness following de novo infection of primary human endothelial cells are in part dependent on KSHV suppression of DUSP1 expression during de novo infection. KSHV-encoded miR-K12-11 upregulates the expression of xCT (an amino acid transporter and KSHV fusion/entry receptor), and existing data indicate a role for xCT in the regulation of 14-3-3β, a transcriptional repressor of DUSP1. We found that miR-K12-11 induces endothelial cell secretion of promigratory factors and cell invasiveness through upregulation of xCT-dependent, 14-3-3β-mediated suppression of DUSP1. Finally, proof-of-principle experiments revealed that pharmacologic upregulation of DUSP1 inhibits the induction of promigratory factors and cell invasiveness during de novo KSHV infection. These data reveal an indirect role for miR-K12-11 in the regulation of DUSP1 and downstream pathogenesis. |
| Databáze: | OpenAIRE |
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