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

Amanda W. Rushing (1) , Blake Rushing , Kimson Hoang (1) , Stephanie Sanders , Jean-Marie Peloponese (2) , Nicholas Polakowski (1) , Isabelle Lemasson (3)

1 Brody School of Medicine - Department of Microbiology and Immunology [Greenville, SC, USA]
2 IRIM - Institut de Recherche en Infectiologie de Montpellier
3 ECU - East Carolina University [Greenville]

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 hematopoi-etic 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 anti-oxidant 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.

Domaines: Biochimie, Biologie Moléculaire; Biologie moléculaire

Amanda W. Rushing, Blake Rushing, Kimson Hoang, Stephanie Sanders, Jean-Marie Peloponese, et al.. HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I. PLoS Pathogens, 2019, 15 (6), pp.e1007922. ⟨10.1371/journal.ppat.1007922⟩. ⟨hal-02347284⟩