title: Kaposi Sarcoma Herpesvirus Induces HO-1 during De Novo Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms.
abstract: Kaposi sarcoma (KS) herpesvirus (KSHV) infection of endothelial cells (EC) is associated with strong induction of heme oxygenase-1 (HO-1), a stress-inducible host gene that encodes the rate-limiting enzyme responsible for heme catabolism. KS is an angioproliferative tumor characterized by the proliferation of KSHV-infected spindle cells, and HO-1 is highly expressed in such cells. HO-1 converts the pro-oxidant, proinflammatory heme molecule into metabolites with antioxidant, anti-inflammatory, and proliferative activities. Previously published work has shown that KSHV-infected EC in vitro proliferate in response to free heme in a HO-1-dependent manner, thus implicating virus-enhanced HO-1 activity in KS tumorigenesis. The present study investigated the molecular mechanisms underlying KSHV induction of HO-1 in lymphatic EC (LEC), which are the likely spindle cell precursors. In a time course analysis of KSHV-infected cells, HO-1 expression displays biphasic kinetics characterized by an early transient induction that is followed by a more sustained upregulation coincident with the establishment of viral latency. A viral microRNA miR-K12-11 deletion mutant of KSHV was found to be defective for induction of HO-1 during latency. A potential mechanism for this phenotype was provided by BACH1, a cellular HO-1 transcriptional repressor targeted by miR-K12-11. In fact, in KSHV-infected LEC, the BACH1 message level is reduced, BACH1 subcellular localization is altered, and miR-K12-11 mediates the inverse regulation of HO-1 and BACH1 during viral latency. Interestingly, the data indicate that neither miR-K12-11 nor de novo KSHV gene expression is required for the burst of HO-1 expression observed at early times postinfection, which suggests that additional virion components promote this phenotype.
  
  
  OBJECTIVE
  While the mechanisms underlying KSHV induction of HO-1 remain unknown, the cellular mechanisms that regulate HO-1 expression have been extensively investigated in the context of basal and pathophysiological states. The detoxifying action of HO-1 is critical for the protection of cells exposed to high heme levels. KS spindle cells are erythrophagocytic and contain erythrocyte ghosts. Erythrocyte degeneration leads to the localized release of heme, creating oxidative stress that may be further exacerbated by environmental or other cofactors. Our previous work showed that KSHV-infected cells proliferate in response to heme and that this occurs in a HO-1-dependent manner. We therefore hypothesize that KSHV induction of HO-1 contributes to KS tumor development via heme metabolism and propose that HO-1 be evaluated as a therapeutic target for KS. Our present work, which aimed to understand the mechanisms whereby KSHV induces HO-1, will be important for the design and implementation of such a strategy.
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Botto
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Totonchy
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.
authors.forename: Jean K
authors.initials: JK
authors.lastname: Gustin
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA mosesa@ohsu.edu.
authors.forename: Ashlee V
authors.initials: AV
authors.lastname: Moses
mesh_terms: D042783:Endothelial Cells / Q000821:virology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D054884:Host-Pathogen Interactions; D035683:MicroRNAs / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism*; D015854:Up-Regulation; D017735:Virus Latency
chemical_list: D035683:MicroRNAs; D012367:RNA, Viral; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1