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HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I

Adult T-cell Leukemia (ATL) is a lymphoproliferative disease of CD4(+) T-cells infected with Human T-cell Leukemia Virus type I (HTLV-1). With the exception of allogeneic hematopoietic stem cell transplantation, there are no effective treatments to cure ATL, and ATL cells often acquire resistance to...

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Autores principales: Rushing, Amanda W., Rushing, Blake, Hoang, Kimson, Sanders, Stephanie V., Péloponèse, Jean-Marie, Polakowski, Nicholas, Lemasson, Isabelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6623464/
https://www.ncbi.nlm.nih.gov/pubmed/31251786
http://dx.doi.org/10.1371/journal.ppat.1007922
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author Rushing, Amanda W.
Rushing, Blake
Hoang, Kimson
Sanders, Stephanie V.
Péloponèse, Jean-Marie
Polakowski, Nicholas
Lemasson, Isabelle
author_facet Rushing, Amanda W.
Rushing, Blake
Hoang, Kimson
Sanders, Stephanie V.
Péloponèse, Jean-Marie
Polakowski, Nicholas
Lemasson, Isabelle
author_sort Rushing, Amanda W.
collection PubMed
description Adult T-cell Leukemia (ATL) is a lymphoproliferative disease of CD4(+) T-cells infected with Human T-cell Leukemia Virus type I (HTLV-1). With the exception of allogeneic hematopoietic stem cell transplantation, there are no effective treatments to cure ATL, and ATL cells often acquire resistance to conventional chemotherapeutic agents. Accumulating evidence shows that development and maintenance of ATL requires key contributions from the viral protein, HTLV-1 basic leucine zipper factor (HBZ). In this study we found that HBZ activates expression of Heme Oxygenase 1 (HMOX-1), a component of the oxidative stress response that functions to detoxify free heme. Transcription of HMOX1 and other antioxidant genes is regulated by the small Mafs. These cellular basic leucine zipper (bZIP) factors control transcription by forming homo- or heterodimers among themselves or with other cellular bZIP factors that then bind Maf responsive elements (MAREs) in promoters or enhancers of antioxidant genes. Our data support a model in which HBZ activates HMOX1 transcription by forming heterodimers with the small Mafs that bind MAREs located in an upstream enhancer region. Consistent with this model, we found that HMOX-1 is upregulated in HTLV-1-transformed T-cell lines and confers these cells with resistance to heme-induced cytotoxicity. In this context, HBZ-mediated activation of HMOX-1 expression may contribute to resistance of ATL cells to certain chemotherapeutic agents. We also provide evidence that HBZ counteracts oxidative stress caused by two other HTLV-1-encoded proteins, Tax and p13. Tax induces oxidative stress as a byproduct of driving mitotic expansion of infected cells, and p13 is believed to induce oxidative stress to eliminate infected cells that have become transformed. Therefore, in this context, HBZ-mediated activation of HMOX-1 expression may facilitate transformation. Overall, this study characterizes a novel function of HBZ that may support the development and maintenance of ATL.
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spelling pubmed-66234642019-07-25 HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I Rushing, Amanda W. Rushing, Blake Hoang, Kimson Sanders, Stephanie V. Péloponèse, Jean-Marie Polakowski, Nicholas Lemasson, Isabelle PLoS Pathog Research Article Adult T-cell Leukemia (ATL) is a lymphoproliferative disease of CD4(+) T-cells infected with Human T-cell Leukemia Virus type I (HTLV-1). With the exception of allogeneic hematopoietic stem cell transplantation, there are no effective treatments to cure ATL, and ATL cells often acquire resistance to conventional chemotherapeutic agents. Accumulating evidence shows that development and maintenance of ATL requires key contributions from the viral protein, HTLV-1 basic leucine zipper factor (HBZ). In this study we found that HBZ activates expression of Heme Oxygenase 1 (HMOX-1), a component of the oxidative stress response that functions to detoxify free heme. Transcription of HMOX1 and other antioxidant genes is regulated by the small Mafs. These cellular basic leucine zipper (bZIP) factors control transcription by forming homo- or heterodimers among themselves or with other cellular bZIP factors that then bind Maf responsive elements (MAREs) in promoters or enhancers of antioxidant genes. Our data support a model in which HBZ activates HMOX1 transcription by forming heterodimers with the small Mafs that bind MAREs located in an upstream enhancer region. Consistent with this model, we found that HMOX-1 is upregulated in HTLV-1-transformed T-cell lines and confers these cells with resistance to heme-induced cytotoxicity. In this context, HBZ-mediated activation of HMOX-1 expression may contribute to resistance of ATL cells to certain chemotherapeutic agents. We also provide evidence that HBZ counteracts oxidative stress caused by two other HTLV-1-encoded proteins, Tax and p13. Tax induces oxidative stress as a byproduct of driving mitotic expansion of infected cells, and p13 is believed to induce oxidative stress to eliminate infected cells that have become transformed. Therefore, in this context, HBZ-mediated activation of HMOX-1 expression may facilitate transformation. Overall, this study characterizes a novel function of HBZ that may support the development and maintenance of ATL. Public Library of Science 2019-06-28 /pmc/articles/PMC6623464/ /pubmed/31251786 http://dx.doi.org/10.1371/journal.ppat.1007922 Text en © 2019 Rushing et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Rushing, Amanda W.
Rushing, Blake
Hoang, Kimson
Sanders, Stephanie V.
Péloponèse, Jean-Marie
Polakowski, Nicholas
Lemasson, Isabelle
HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I
title HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I
title_full HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I
title_fullStr HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I
title_full_unstemmed HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I
title_short HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I
title_sort htlv-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of heme oxygenase i
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6623464/
https://www.ncbi.nlm.nih.gov/pubmed/31251786
http://dx.doi.org/10.1371/journal.ppat.1007922
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