HTLV-1 bZIP factor protein targets the Rb/E2F-1 pathway to promote proliferation and apoptosis of primary CD4+ T cells

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that induces a fatal T-cell malignancy, adult T-cell leukemia (ATL). Among several regulatory/accessory genes in HTLV-1, HTLV-1 bZIP factor (HBZ) is the only viral gene constitutively expressed in infected cells. Our previous study showed that HBZ functions in two different molecular forms, HBZ protein and HBZ RNA. In this study, we show that HBZ protein targets retinoblastoma protein (Rb), which is a critical tumor suppressor in many types of cancers. HBZ protein interacts with the Rb/E2F-1 complex and activates the transcription of E2F-target genes associated with cell cycle progression and apoptosis. Mouse primary CD4+ T cells transduced with HBZ show accelerated G1/S transition and apoptosis, and importantly, T cells from HBZ transgenic (HBZ-Tg) mice also demonstrate enhanced cell proliferation and apoptosis. To evaluate the functions of HBZ protein alone in vivo, we generated a new transgenic mouse strain that expresses HBZ mRNA altered by silent mutations but encoding intact protein. In these mice, the numbers of effector/memory and Foxp3+ T cells were increased, and genes associated with proliferation and apoptosis were upregulated. This study shows that HBZ protein promotes cell proliferation and apoptosis in primary CD4+ T cells through activation of the Rb/E2F pathway, and that HBZ protein also confers onto CD4+ T-cell immunophenotype similar to those of ATL cells, suggesting that HBZ protein has important roles in dysregulation of CD4+ T cells infected with HTLV-1.

Human T-cell leukaemia virus type 1: parasitism and pathogenesis

“…HBZ perturbs the localization and function of FoxO3a, a critical transcriptional activator of the genes encoding Bim and also Fas ligand, which results in inhibited apoptosis [ 69 ]. HBZ also interacts with the Rb/E2F-1 complex and promotes cell cycle progression [ 70 ]. Furthermore, HBZ determines the immunophenotype of infected cells, including ATL cells: HBZ induces expression on the cell surface of TIGIT and CCR4 [ 71 , 72 ], which are implicated in the infiltration and proliferation of HTLV-1-infected cells.…”

HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

“…Soon after ATL cells were found to persistently express HBZ, but not Tax, both HBZ RNA and protein were shown to stimulate T-cell proliferation. Recent data indicate that HBZ protein additionally promotes apoptosis induction, while HBZ mRNA prevents it, in part via up-regulation of the survivin gene [ 138 ]. Importantly, CD4+ T lymphocyte-specific expression of the HBZ transgene in mice induces T-cell lymphoma and systemic inflammation [ 8 ].…”

“…HBZ protein also assists JunD in the transcriptional activation of human telomerase reverse transcriptase (hTERT) [ 141 ]. Recent results indicate that HBZ protein can target the retinoblastoma protein (Rb)/ E2F transcription factor 1 (E2F1) complex to activate the transcription of genes under E2F1 control that are critical for DNA replication and cell cycle progression [ 138 ]. The activation of E2F-regulated genes by HBZ promotes both T-cell proliferation and apoptosis.…”

Future Perspectives on Drug Targeting in Adult T Cell Leukemia-Lymphoma

“…Thus, Tax is likely required to initiate leukemogenesis while its expression is not routinely detected later in fresh cells from at least 50% of patients with established ATL. Recent data, however, demonstrated that survival of ATL cells depend on transient tax expression ( Dassouki et al, 2015 ; Mahgoub et al, 2018 ) Conversely, HBZ is persistently expressed, even if at low level, in vivo in ATL cells, and interacts with elongation factors, Rb/E2F-1 complex, for cell cycle progression ( Kawatsuki et al, 2016 ), inhibits apoptosis and upregulates expression of CCR4, thus promoting proliferation and migration of T cells ( Sugata et al, 2016 ) and finally inducing global epigenetic changes in infected cells. In addition epigenetic dysregulation plays a role in ATL transformation consisting in GpC methylation of cell cycle, p53, apoptotic genes and histone modification of epigenetic reprogramming genes ( Watanabe, 2017 ).…”