The HBZ-SP1 isoform of human T-cell leukemia virus type I represses JunB activity by sequestration into nuclear bodies
© Hivin et al; licensee BioMed Central Ltd. 2007
Received: 20 November 2006
Accepted: 16 February 2007
Published: 16 February 2007
The human T-cell leukemia virus type I (HTLV-I) basic leucine-zipper factor (HBZ) has previously been shown to modulate transcriptional activity of Jun family members. The presence of a novel isoform of HBZ, termed HBZ-SP1, has recently been characterized in adult T-cell leukemia (ATL) cells and has been found to be associated with intense nuclear spots. In this study, we investigated the role of these nuclear bodies in the regulation of the transcriptional activity of JunB.
Using fluorescence microscopy, we found that the HBZ-SP1 protein localizes to intense dots corresponding to HBZ-NBs and to nucleoli. We analyzed the relative mobility of the EGFP-HBZ-SP1 fusion protein using fluorescence recovery after photobleaching (FRAP) analysis and found that the deletion of the ZIP domain perturbs the association of the HBZ-SP1 protein to the HBZ-NBs. These data suggested that HBZ needs cellular partners, including bZIP factors, to form HBZ-NBs. Indeed, by cotransfection experiments in COS cells, we have found that the bZIP factor JunB is able to target delocalized form of HBZ (deleted in its nuclear localization subdomains) into the HBZ-NBs. We also show that the viral protein is able to entail a redistribution of JunB into the HBZ-NBs. Moreover, by transfecting HeLa cells (known to express high level of JunB) with a vector expressing HBZ-SP1, the sequestration of JunB to the HBZ-NBs inhibited its transcriptional activity. Lastly, we analyzed the nuclear distribution of HBZ-SP1 in the presence of JunD, a Jun family member known to be activated by HBZ. In this case, no NBs were detected and the HBZ-SP1 protein was diffusely distributed throughout the nucleoplasm.
Our results suggest that HBZ-mediated sequestration of JunB to the HBZ-NBs may be causing the repression of JunB activity in vivo.
Human T-cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus etiologically associated with the development of adult T-cell leukemia (ATL) [1, 2]. The mechanisms behind leukemogenesis are not yet fully understood but it seems that several events in HTLV-I-infected cells are required for the development of the full malignant phenotype. Among them, the expression of the viral Tax protein plays a crucial role in the first steps of the process [3, 4]. Tax has the ability to deregulate the transcription of genes and signaling pathways involved in cellular proliferation, cell cycle control and apoptosis, including deregulation of the activator protein-1 (AP-1), nuclear factor-κB, and E2F pathways .
AP-1 represents a dimeric protein, consisting of homodimers and heterodimers composed of basic region-leucine zipper (bZIP) proteins. AP-1 can be formed through either homodimerization of Jun proteins (c-Jun, JunB, and JunD) or heterodimerization of Jun and Fos proteins (c-Fos, FosB, Fra-1, and Fra-2) via their respective ZIP domain . In addition, Jun proteins can heterodimerize with different members of the bZIP protein family including the dimerization partners JDP1 and JDP2 , activating transcription factors , and Maf proteins . In unstimulated T cells, the basal protein level of AP-1 is low but there is a rapid induction of AP-1 activity after T-cell stimulation. The IL-2 gene was one of the first T-cell-specific genes shown to have an AP-1 site within its promoter . The AP-1 transcription complex has been shown to be involved in the regulation of IL-2 gene expression in combination with other transcription factors . The production of IL-2 by activated T cells is critical for T-cell proliferation and differentiation, and the development of T-cell-dependent immune responses. Over the recent years, a large quantity of data has accumulated demonstrating the contribution of AP-1 to the regulation of numerous cellular genes involved in lymphocyte activation.
AP-1 is also involved in the dysregulated phenotypes of T cells infected with HTLV-I [12, 13]. Previous studies have shown that T-cell lines infected by HTLV-I express high levels of AP-1 activity [14, 15] with increased levels of mRNAs coding for c-Jun, JunB, JunD, c-Fos, and Fra-1 [16, 17]. Indeed, Tax can induce the expression of the genes encoding c-Fos, Fra-1, c-Jun, and JunD [16, 18]. In addition, it has been recently demonstrated that Tax enhances AP-1 activity at the post-transcriptional level by activating protein kinase B . Moreover, AP-1-binding sites have been shown to be responsive elements targeted by Tax in different cellular genes such as fra-1 and IL-2 [20, 21]. On the other hand, most of ATL cells do not express significant level of Tax in vivo suggesting that constitutive activation of AP-1 in leukemic cells is likely Tax independent , although it cannot be completely excluded that a trace amount of Tax may be sufficient for AP-1 activation. However, recent data have suggested the involvement of another viral protein in the regulation of AP-1 activity, i.e. the HTLV-I bZIP factor (HBZ) .
In this paper, we describe the nuclear distribution of the new HBZ isoform and we show that the HBZ-SP1 protein not only accumulates in particular nuclear bodies (called here HBZ-NBs) as already described for the original HBZ isoform, but that it is also targeted to nucleoli. Moreover, we have studied the in vivo nuclear dynamics of the HBZ-NBs through fluorescence recovery after photobleaching (FRAP) experiments on cells transfected with the expression vector encoding HBZ-SP1 fused to the enhanced-green-fluorescent protein (EGFP). We have observed that the rate of nuclear flux of the HBZ-SP1 protein is altered by the deletion of its leucine zipper domain, suggesting that its heterodimerization partners are involved in controlling its own nuclear trafficking. Indeed, by cotransfection experiments in COS cells, we have found that JunB targets a mutated and delocalized form of HBZ into the HBZ-NBs. In addition, we show that HBZ-SP1 also modifies the localization of exogenous JunB in cotransfected COS cells and targets JunB to the HBZ-NBs. Moreover, we demonstrate in HeLa cells (known to have high expression level of JunB) that the relocalization of endogenous JunB by HBZ-SP1 into HBZ-NBs inhibits its transcriptional activity. Taken together, these results clearly demonstrate that HBZ-mediated sequestration of JunB to these particular subnuclear structures may result in repression of JunB activity.
The HBZ-SP1 isoform shows a characteristic nuclear distribution
It has recently been shown that the HBZ-SP1 isoform was preferentially expressed in ATL cell lines . For this reason, it was of high interest to investigate the subnuclear distribution of this protein in vivo. COS cells were transfected with vectors expressing the original HBZ and HBZ-SP1 isoforms tagged with the Myc epitope fused to its C-terminal end. As shown in (Fig. 1A, a and 1A, b), the subnuclear distribution of the HBZ-SP1 isoform exhibits a NB-associated granular distribution as already described for the original HBZ isoform . We had also shown that this particular nuclear distribution did not correspond to the splicing factor compartments . To determine whether it was also the case for the HBZ-SP1 protein, we next checked the staining pattern of HBZ-SP1 (tagged with EGFP fused to its N-terminus) with that seen in the same cell stained with anti-SC35, an antibody that recognizes one component of an active spliceosome. We found that the HBZ-SP1 isoform did not colocalize with the endogenous SC35 (Fig. 1B).
FRAP analysis of the subnuclear transport of HBZ-SP1
To determine the influence of HBZ-SP1 cellular partners on its intracellular mobility, we decided to perform FRAP analysis with EGFP fused to the mutant HBZ-SP1ΔZIP. Interestingly, compared with the wild type, the mutant showed a different pattern of staining since HBZ-SP1ΔZIP-associated structures were more diffuse. As shown in Fig. 2, colocalization experiments carried out with an anti-nucleolin antibody demonstrated that these nuclear structures corresponded to nucleoli displaying a branching structure. These data suggest that the integrity of the viral protein is required for the formation of the HBZ-NBs. Moreover, while the estimated half-time for signal recovery was the same for EGFP-HBZ-SP1 and EGFP-HBZ-SP1ΔZIP, the mean percentage of mobile fraction of EGFP-HBZ-SP1ΔZIP only was 16.4 ± 1.5% (Fig. 3). The decreased mobility of the HBZ-SP1ΔZIP protein compared with the full-length protein also suggested that deletion of the ZIP domain perturbs the intracellular mobility of HBZ-SP1 protein. In conclusion, one plausible interpretation for these observations is that HBZ needs cellular partners, including bZIP factors, to form HBZ-NBs.
Association of HBZ-SP1 with JunB is involved in the formation of HBZ-NBs
HBZ-NBs are involved in the repression of JunB activity by HBZ-SP1
The HBZ-SP1 protein does not form HBZ-NBs in the presence of JunD
In this paper, we have studied the nuclear distribution of the HBZ-SP1 isoform produced from the HBZ-SP1 spliced transcript initiated in the 3' long terminal repeat of the HTLV-I proviral genome [24, 25]. The HBZ-SP1 mRNA has been described to be the most abundant HBZ spliced variant detected in different HTLV-I-infected cell lines and importantly in cellular clones isolated from HTLV-I-infected patients [24–26]. In addition, by immunoblot analyses and immunochemistry, Murata et al. have recently demonstrated that the ATL cell lines predominantly express HBZ-SP1 isoform at the protein level . They have also observed that the HBZ-SP1 protein can be located in the nucleoli  in addition to its association with particular NBs, which have been already described for the original HBZ isoform . Our data here confirm their observations since, in transfected COS cells, the EGFP-HBZ-SP1 fusion protein is effectively located in the nucleoli. Moreover, although we have previously demonstrated that the original HBZ could be associated with heterochromatin distributed around the nucleoli , we found no association of the HBZ-SP1 protein with heterochromatin markers (data not shown). The location of the HBZ-SP1 protein in the nucleoli is not unexpected since we have previously demonstrated that HBZ possesses two basic regions, BR1 and BR2, positioned upstream of its bZIP domain, which are similar in sequence to the consensus nucleolar localization signal and are able to target EGFP to nucleoli . The functional role for this particular subcellular targeting remains however unclear. The nucleolus has been described to be involved in the sequestration of transcription factors, such as hypoxia-inducible factor-1α, as well as of proteins that modulate transcription factor activity, such as Mdm2 [38, 39]. Therefore, we cannot exclude the possibility that nucleolar proteins can regulate the function of the HBZ-SP1 protein. Conversely, it could be suggested that the HBZ-SP1 protein might act on nucleolar proteins, especially knowing that this viral protein has been shown to be located in nucleoli of ATL cell lines .
In addition to BR1 and BR2, a third NLS region corresponding to the basic domain of the HBZ bZIP has been characterized . However, the presence of at least two of the three NLSs is necessary for the translocation of this protein to the nucleus. In this study, we confirm these previous observations since the EGFP-HBZ bZIP fusion protein exhibits a diffuse distribution throughout the cytoplasm and the nucleus. On the other hand, in the presence of JunB, nuclear accumulation of HBZ bZIP is stimulated. Moreover, our results indicate that HBZ bZIP is efficiently targeted into HBZ-NBs by interaction with JunB. On the other hand, this interaction causes targeting of both proteins into NBs and not into the nucleoli, confirming that BR1 and BR2 are likely to be involved in the transport of the viral protein into the nucleoli. In addition, we find that HBZ-NBs do not colocalize with nuclear proteins known to be associated with active transcriptional sites. Effectively, in HeLa cells transfected with EGFP-HBZ-SP1 fusion protein, we have demonstrated that the relocalization of endogenous JunB into HBZ-NBs is associated with repression of its activity. It is worth noting that we have previously demonstrated that the DNA-binding activity of JunB on AP-1 site is inhibited in the presence of HBZ . Taken together, our results suggest that the HBZ-SP1 protein could inhibit JunB activity by forming a heterodimer unable to bind to viral or cellular promoters and by targeting JunB to HBZ-NBs. This hypothesis is confirmed by the data obtained with JunD. Indeed, HBZ stimulates JunD transcriptional activity , does not modify its DNA-binding activity , and is diffusely distributed throughout the nucleus in the presence of JunD. The latter result differs from a previous study performed in our laboratory. We had found that HBZ entailed an intracellular redistribution of JunD into NBs . We speculate that this difference may be related to the fact that JunD was tagged with RFP, which has impaired the JunD transcriptional activity in vivo (our unpublished data). Henceforth, it would be of high interest to determine whether other nuclear proteins could be associated with the HBZ-NBs. For the moment, we have tested different proteins including PML, SC35, HP1α, HP1β, HP1γ, and HMGA1a (data not shown), and none of these proteins demonstrated colocalization with the HBZ-SP1 protein. These particular nuclear structures could also correspond to sites promoting protein degradation as suggested by Matsumoto et al.  or protein modification as already described for members of the protein inhibitor of activated STAT family . Complementary experiments are necessary to evaluate these different possibilities.
We and others have already demonstrated that the HBZ bZIP domain is involved in the interaction with the different members of the Jun family [30, 31]. In this study, we further extend these observations with our results on JunB. From our studies, it is apparent that HBZ is capable of inhibiting both c-Jun and JunB transcriptional activities while it stimulates JunD activity. Thus, HBZ provides an interesting model to better understand the consequences of a dysfunction of the AP-1 pathway in T cells. Future experiments focussed on the regulation of HBZ expression and activity will also be of great interest. Moreover, the identification of putative cellular genes controlled by this novel AP-1 factor should elucidate the diverse regulatory properties of HBZ and its exact function in the development of ATL.
The vectors pcDNA-HBZ-SP1-Myc, pEGFP-HBZ-bZIP (Fig. 1A), pcDNA-JunB, pCMV-JunD-Flag have already been described [23, 25, 30]. To generate the EGFP fusion proteins, HBZ-SP1, HBZ-SP1ΔZIP, HBZΔAD, and HBZΔADΔbZIP DNA (Fig. 1A) were PCR amplified from the pcDNA-HBZ-SP1-Myc vector, digested with EcoRI and BamHI, and subcloned in frame into similarly digested pEGFP-C2 (Clontech). pEGFP-HBZΔAD and pEGFP-HBZΔADΔbZIP encode for the HBZ-SP1 protein from residues 77 to 206 and 77 to 132, respectively. pLCR-Luc and pNLS-EGFP (corresponding to EGFP under the control of the nuclear localization signal of SV40) is a gift from G. Steger and M. Piechaczyk, respectively.
Fluorescence microscopy analysis
COS cells were cultured in DMEM supplemented with 10% FCS. 24 h before transfection, cells were seeded onto glass slides. They were transfected using the jetPEI™ transfection reagent (Qbiogene) according to the manufacturer's instructions and, after 48 h, they were washed with PBS, fixed, and permeabilized with 4% paraformaldehyde and 0.1% Triton ×-100 for 30 min at room temperature. If necessary, cells were incubated with primary antibody (mouse anti-Myc antibody 9E10 or anti-Flag, Sigma-Aldrich; mouse anti-nucleolin, anti-JunB, or anti-RNA polymerase II antibody, Santa Cruz Biotechnology Inc.; the mouse anti-SC35 antibody is a gift from J. Tazi) for 1 h at room temperature. Samples were washed with PBS and then incubated with secondary FITC- or Texas Red-labelled antibodies (Pierce) for 1 h at room temperature. Coverslips were mounted with Vectashield containing DAPI (Abcys) for direct observation.
Fluorescence images were acquired by fluorescence microscopy (model DM R; Leica) at room temperature with a 63x, NA 1.32, oil immersion objective at pinhole size 1 Airy (observation with immersion oil type DF, Cargille Laboratories Inc.). DAPI, GFP, FITC, and Texas Red were excited by 365-, 488-, 492-, and 596-nm laser light and emission was detected at 420, 507, 520, and 620 nm, respectively. The photographs were taken with a Photo Leika DC 250 camera and the images were analyzed with QFluoro software (Leica).
FRAP was performed using the Zeiss LSM Meta 510 confocal microscope. FRAP recoveries were acquired at 37°C on EGFP-HBZ-SP1- or EGFP-HBZ-SP1ΔZIP-expressing cells plated on glass coverslips. The 488-nm line of the Ar+ laser was used for the excitation of EGFP. Cells were observed using a 63x, NA 1.2, oil immersion objective at pinhole size 1 Airy (observation with immersion oil Immersol™, Zeiss). After 5 prebleach scans, a region of interest was bleached and fluorescence recovery was analyzed for 5 min. Experimental recoveries were normalized and corrected for z-position fluctuation of cells using another region as an internal standard.
HeLa cell transfection and luciferase assay
HeLa cells were cultured in DMEM supplemented with 10% FCS and were transfected using the jetPEI™ transfection reagent (Qbiogene). 1 μg of pcDNA3.1(-)/Myc-His/lacZ (β-galactosidase-containing reference plasmid) was included in each transfection to control for transfection efficiency. The total amount of DNA in each transfection was the same (3.6 μg) through the adequate added amount of pcDNA3.1(-)/Myc-His. Cell extracts normalized for protein content were used for luciferase and β-galactosidase assays as already described .
Cell cycle analysis by flow cytometry
Cell cycle analysis was based on the measurement of nuclear DNA content using flow cytometry and propidium iodide. Briefly, HeLa cells were trypsinized, washed with PBS, and fixed in cold 70% ethanol. After being washed in PBS, cells were resuspended in PBS containing 0.1% Triton ×-100, 40 μg/ml propidium iodide, and 50 μg/ml RNase A. Stained cells were then processed with an EPICS XL4C cytofluorometer (Coulter) and analyzed with the CellCycle software. For flow cytometric analysis of transiently transfected cells, 106 HeLa cells were transfected with 5 μg of pNLS-EGFP or pEGFP-HBZ-SP1 using the BD Calphos™ mammalian transfection kit (BD Biosciences) according to the manufacturer's instructions. At 24 h posttransfection, cells were harvested and GFP-positive cells were then analyzed for DNA content with a UV laser by the EPICS XL4C cytofluorometer (Coulter). For analyses of S-phase entry, the cells were arrested by using a double thymidine block. The HeLa cells were blocked for 12h with 2,5 mM thymidine, washed with DMEM without serum, transfected with the indicated vector and, at 12 h posttransfection, cells were again blocked with 2,5 mM thymidine for another 12 h to arrest all cells at the beginning of S phase. The cells were released from the thymidine block by three washes in fresh medium and allowed to progress through G1 and into S phase by stimulation with 10% FCS. The cell cycle positioning of serum-stimulated cells was determined at different time points by propidium iodide staining and flow cytometry analysis as described above.
adult T-cell leukemia
basic region-leucine zipper
fluorescence recovery after photobleaching
human T-cell leukaemia virus type I
We thank Pierre Travo (Montpellier Rio Imaging) and Isabelle Jariel-Encontre for technical assistance. This work was supported by institutional grants from the Centre National de la Recherche Scientifique (CNRS) and the Université Montpellier I (UM I), grants to J.M.M. from the Association pour la Recherche sur le Cancer (ARC n° 3606), and grants to B.B. from The Cancer Research Society Inc.. P.H. and F.R. are supported by a fellowship from the Association pour la Recherche sur le Cancer and from the Ambassy of France in Canada, respectively. We thank J. Tazi for the kind gift of the anti-SC35 antibody.
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