Kaposi Sarcoma Herpesvirus Induces HO-1 during <italic toggle="yes">De Novo</italic> 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 t...

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Autores principales:	Sara Botto, Jennifer E. Totonchy, Jean K. Gustin, Ashlee V. Moses
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/71d738a75a394381a51ab4e24220fb7d
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spelling	oai:doaj.org-article:71d738a75a394381a51ab4e24220fb7d2021-11-15T15:49:02ZKaposi Sarcoma Herpesvirus Induces HO-1 during <italic toggle="yes">De Novo</italic> Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms10.1128/mBio.00668-152150-7511https://doaj.org/article/71d738a75a394381a51ab4e24220fb7d2015-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00668-15https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Sara BottoJennifer E. TotonchyJean K. GustinAshlee V. MosesAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 3 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Sara Botto Jennifer E. Totonchy Jean K. Gustin Ashlee V. Moses Kaposi Sarcoma Herpesvirus Induces HO-1 during <italic toggle="yes">De Novo</italic> Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms
description	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. IMPORTANCE 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.
format	article
author	Sara Botto Jennifer E. Totonchy Jean K. Gustin Ashlee V. Moses
author_facet	Sara Botto Jennifer E. Totonchy Jean K. Gustin Ashlee V. Moses
author_sort	Sara Botto
title	Kaposi Sarcoma Herpesvirus Induces HO-1 during <italic toggle="yes">De Novo</italic> Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms
title_short	Kaposi Sarcoma Herpesvirus Induces HO-1 during <italic toggle="yes">De Novo</italic> Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms
title_full	Kaposi Sarcoma Herpesvirus Induces HO-1 during <italic toggle="yes">De Novo</italic> Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms
title_fullStr	Kaposi Sarcoma Herpesvirus Induces HO-1 during <italic toggle="yes">De Novo</italic> Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms
title_full_unstemmed	Kaposi Sarcoma Herpesvirus Induces HO-1 during <italic toggle="yes">De Novo</italic> Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms
title_sort	kaposi sarcoma herpesvirus induces ho-1 during <italic toggle="yes">de novo</italic> infection of endothelial cells via viral mirna-dependent and -independent mechanisms
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/71d738a75a394381a51ab4e24220fb7d
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Kaposi Sarcoma Herpesvirus Induces HO-1 during <italic toggle="yes">De Novo</italic> Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms

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