title: Kaposi's sarcoma-associated herpesvirus suppression of DUSP1 facilitates cellular pathogenesis following de novo infection.
abstract: 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.
authors.affiliation: Research Center for Translational Medicine and Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Qin
authors.forename: Lu
authors.initials: L
authors.lastname: Dai
authors.forename: Michael
authors.initials: M
authors.lastname: Defee
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Findlay
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Watson
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Toole
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cameron
authors.forename: Francesca
authors.initials: F
authors.lastname: Peruzzi
authors.forename: Keith
authors.initials: K
authors.lastname: Kirkwood
authors.forename: Chris
authors.initials: C
authors.lastname: Parsons
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D012367:RNA, Viral; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1