Abstract
BackgroundTax is the oncoprotein of HTLV-1 which deregulates signal transduction pathways, transcription of genes and cell cycle regulation of host cells. Transacting function of Tax is mainly mediated by its protein-protein interactions with host cellular factors. As to Tax-mediated regulation of gene expression of HTLV-1 and cellular genes, Tax was shown to regulate histone acetylation through its physical interaction with histone acetylases and deacetylases. However, functional interaction of Tax with histone methyltransferases (HMTase) has not been studied. Here we examined the ability of Tax to interact with a histone methyltransferase SUV39H1 that methylates histone H3 lysine 9 (H3K9) and represses transcription of genes, and studied the functional effects of the interaction on HTLV-1 gene expression.ResultsTax was shown to interact with SUV39H1 in vitro, and the interaction is largely dependent on the C-terminal half of SUV39H1 containing the SET domain. Tax does not affect the methyltransferase activity of SUV39H1 but tethers SUV39H1 to a Tax containing complex in the nuclei. In reporter gene assays, co-expression of SUV39H1 represses Tax transactivation of HTLV-1 LTR promoter activity, which was dependent on the methyltransferase activity of SUV39H1. Furthermore, SUV39H1 expression is induced along with Tax in JPX9 cells. Chromatin immunoprecipitation (ChIP) analysis shows localization of SUV39H1 on the LTR after Tax induction, but not in the absence of Tax induction, in JPX9 transformants retaining HTLV-1-Luc plasmid. Immunoblotting shows higher levels of SUV39H1 expression in HTLV-1 transformed and latently infected cell lines.ConclusionOur study revealed for the first time the interaction between Tax and SUV39H1 and apparent tethering of SUV39H1 by Tax to the HTLV-1 LTR. It is speculated that Tax-mediated tethering of SUV39H1 to the LTR and induction of the repressive histone modification on the chromatin through H3 K9 methylation may be the basis for the dose-dependent repression of Tax transactivation of LTR by SUV39H1. Tax-induced SUV39H1 expression, Tax-SUV39H1 interaction and tethering to the LTR may provide a support for an idea that the above sequence of events may form a negative feedback loop that self-limits HTLV-1 viral gene expression in infected cells.
Highlights
Tax is the oncoprotein of Human T-cell leukemia virus type 1 (HTLV-1) which deregulates signal transduction pathways, transcription of genes and cell cycle regulation of host cells
HTLV-1 Tax interacts with SUV39H1 To determine whether HTLV-1 Tax has the ability to interact with SUV39H1, we used GST pull-down and coimmunoprecipitation assays by transient transfection of
The results clearly showed that affinity-purified GST-SUV39H1 complex contained HTLV-1 Tax protein, whereas Tax protein was not co-purified with GST alone (Figure 1a)
Summary
Tax is the oncoprotein of HTLV-1 which deregulates signal transduction pathways, transcription of genes and cell cycle regulation of host cells. Transacting function of Tax is mainly mediated by its protein-protein interactions with host cellular factors. Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of an aggressive leukemia known as adult Tcell leukemia (ATL), as well as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and HTLV-1 uveitis (HU). These diseases develop usually after more than 40 years of clinical latency [1,2,3,4]. Tax regulates multiple cellular responses by its protein-protein interactions with various host cellular factors. Tax-mediated transcriptional regulation is based on its interaction with DNA-binding transcription factors such as members of the cyclic AMP response element binding protein/activating transcription factor (CREB/ATF), the nuclear factor-κB (NF-κB), and the serum response factor (SRF) and with two related transcriptional co-activators CREB binding protein (CBP) and p300
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