The Tat protein of HIV-1 induces galectin-3 expression

Séverine Fogel, Michael Guittaut, Alain Legrand, Michel Monsigny and Eric Hébert1

Glycobiology, Centre de Biophysique Moléculaire, UPR no. 4301 du CNRS conventionnée avec l'Université d'Orléans, Rue Charles Sadron, 45071 Orléans Cédex 2, France

Received on July 3, 1998; accepted on August 28, 1998

Animal lectins play important roles in a variety of biological processes via their recognition of glycoconjugates. Galectin-3 is a [beta]-galactoside-binding lectin whose expression is associated with various pathological processes including human T lymphotropic virus (HTLV)-I-infection of human T cell lines and human immunodeficiency virus (HIV) infection of T-lymphoblastic Molt-3 cell line. In the case of HIV-infected cells, it has been suggested that the increase in galectin-3 expression could be related to the expression of the viral regulatory gene tat. These results prompt us to perform more extensive analyses of the relationship between galectin-3 and HIV-1 Tat expressions. In this study, we found that Tat protein expression induces an upregulation of galectin-3 in several human cell lines. In co-transfection experiments, the 5[prime]-regulatory sequences of the galectin-3 gene were significantly upregulated by expression vectors encoding the Tat protein. Analysis performed with 5[prime]-regulatory deleted sequences suggested that galectin-3 induction by Tat is dependent on activation of the Sp-1 binding transcription factor.

Key words: galectin-3/ transactivation /Tat protein/U937

Introduction

Animal lectins are recognized as molecules playing important roles in a variety of biological processes through binding to glycoconjugates (Drickamer, 1988; Sharon and Lis, 1989). Among lectins, galectins (Barondes et al., 1994a,b) are members of a growing family of [beta]-galactoside-binding lectins, and galectin-3 is one of the most extensively studied members. Various functions have been suggested or demonstrated for galectin-3, and it appears that this lectin is a versatile multifunctional protein (see Hughes, 1994, for review). The distribution of galectin-3 is quite diverse, and its expression in various leukocytes has been observed, including neutrophils (Truong et al., 1993a), eosinophils (Truong et al., 1993b), and macrophages (Liu et al., 1995); it has been suggested that it may be a modulator of inflammatory responses and lymphocyte T activation (Dong and Hughes, 1996). Expression of galectin-3 modulates T-cell growth and apoptosis (Yang et al., 1996). T cells infected with human T-cell leukemia virus type I express a high level of galectin-3, in contrast to uninfected cells; this overexpression appears to result from the activation of the galectin-3 promoter by the viral transactivating protein Tax (Hsu et al., 1996). Moreover, galectin-3 may play a role during the initial stage of HIV infection, most likely during transport and/or splicing of HIV mRNA as its expression greatly increases after infection of Molt-3 cells with human immunodeficiency virus type 1, concomitantly with the onset of expression of Tat protein (Schröder et al., 1995).

HIV-1 Tat protein is essential for viral replication by stimulating viral gene expression (Jones, 1993). In addition, Tat regulates the expression of host cellular genes such as those encoding cytokines (Buonaguro et al., 1992; Scala et al., 1994), and cell survival-related proteins including p53 and Bcl-2 (Li et al., 1995; Zauli et al., 1995), therefore modulating biological activities in various cell types, e.g., promoting growth of Kaposi's sarcoma cells (Ensoli et al., 1990). Moreover, Tat can be released from productively infected cells (Ensoli et al., 1992).

These results prompt us to perform more extensive analyses of the relationship between galectin-3 and HIV-1 Tat expressions. In this study, we found that Tat protein expression induces an upregulation of galectin-3 in several human cell lines; this upregulation seems to be the result of a Tat transactivation of Sp-1-rich regulatory sequences upstream of the galectin-3 gene.

Results

Expression of galectin-3 in Tat expression vector-transfected cells

We first examined endogenous galectin-3 protein level in Tat expression vector-transfected human epithelial A549 cell line. Cells were grown on coverslips and transfected with pNAF, a HIV LTR-directed Tat expression vector using the PEI method. Cells were harvested 48 h later and double immunostained using a specific anti-Tat antibody (Figure 1a) and an anti-galectin-3 antibody (Figure 1b). Most of the A549 cells show moderate levels of galectin-3 both in the nucleus and in the cytoplasm. About 1% of cells per microscopic shots were stained for Tat expression, mainly with a nucleolar distribution. All Tat-positive cells exhibited a higher level of galectin-3 protein than did Tat-negative cells. Moreover, the nuclear staining was predominant over the cytoplasmic staining. In order to verify that galectin-3 overexpression in Tat-positive cells was not due to the transfection procedure, a double immunostaining was performed on A549 cells transfected with pSV2luc by using anti-luciferase antibody (Figure 1c) and anti-galectin-3 antibody (Figure 1d). No galectin-3 overexpression was observed in cells expressing luciferase. It is therefore clear that the galectin-3 overexpression in A549 cells was induced by the Tat protein.

With the aim of investigating the influence of Tat on the galectin-3 expression under permissive conditions, the pNAF Tat expression vector was introduced by electroporation in the human U937 promonocytic cell line. This cell type is known to express galectin-3 (Nangia-Makker et al. 1993) and is thus suitable for this purpose. As shown in Figure 2c, non-Tat-expressing U937 cells expressed galectin-3 at a low level. The galectin-3 expression was clearly enhanced in the Tat-expressing cell as shown in Figure 2b using anti-Tat antibody. Therefore, Tat protein is also able to increase the expression of galectin-3 in U937 promonocytic cell line.

Effect of Tat on activity of the rabbit galectin-3 promoter

In order to determine whether Tat protein was able to induce galectin-3 overexpression by interacting with its promoter, cotransfection experiments were performed with A549 cell line using Tat expression vector and a vector harboring the rabbit galectin-3 promoter sequence controlling expression of the GFP reporter gene (Figure 3). In preliminary experiments we determined that the rabbit galectin-3 promoter is fully responsive to Tat by transfecting rabbit Rb-1 cells with the Tat expression vector and then analyzing endogenous galectin-3 protein level by confocal microscopy after double immunostaining (data not shown). Figure 4 shows one Tat-expressing cell that expressed a high level of GFP from pG3-210 vector which contains 10.5 kb upstream of the galectin-3 gene (Figure 3). No GFP expression at levels similar to those observed by Tat induction was detected in any Tat-negative cells. Some Tat-expressing cells do not show GFP expression, probably due to the lack of cotransfection by pG3-210 vector. The pG3-204 vector which contains about 4.5 kb of the 5[prime]-flanking regions of the rabbit galectin-3 gene led also to GFP upregulation in Tat-expressing cells; conversely, the pG3-208 control vector (Figure 3) did not reveal any Tat-induced GFP expression (not shown). Therefore, HIV-1 Tat protein expression led to a marked increase in galectin-3 expression resulting from transactivation on the upstream 4.5 kb promoter sequences.

Discussion

The expression of Tat protein in several cell types led to a marked increase in galectin-3 gene expression. Moreover the results obtained with GFP reporter gene under the control of deleted 5[prime]-flanking sequences of rabbit galectin-3 gene suggest that the activation of galectin-3 gene by the Tat protein involves the Sp1 transcription factor pathways. Inspection of the 5[prime]-flanking sequence of rabbit (Gaudin et al., 1997) and human (Kadrofske et al., 1998) galectin-3 genomic DNA in fact revealed that the promoter does not contain a TATA box immediately upstream of the transcription start site. There are, however, multiple GC box motifs for binding of the ubiquitously expressed Sp1 transcription factor, a common feature seen in the promoters of constitutively expressed, so-called housekeeping genes. It is unusual that the galectin-3 promoter looks like that of a housekeeping gene as it has been rather characterized as an immediate early gene. Nevertheless, Sp1 has been shown to regulate transcription from another immediate early gene, the human adenine nucleotide translocase gene (Li et al., 1996). Sp1 protein is sometimes required for Tat activity in in vitro transcription assay (Sune and Garcia-Blanco, 1995; Zhou and Sharp, 1995); moreover, interaction between Sp1 and Tat has been demonstrated in HIV-1-infected cells (Jeang et al., 1993), and optimal transactivation by Tat (from HIV-2) requires binding sites for Sp1 or Sp1 brought to the promoter by a heterologous system (Pagtakhan and Tong-Starksen, 1997). Tat protein can differentially affects Sp1-responsive promoters, depending on promoter architecture (Howcroft et al. 1995); nevertheless, data are not sufficient today to define the features of the promoter required to predict the Tat-Sp1 effect in terms of activation or repression of gene expression. Whatever is the molecular mechanism of Sp1-mediated Tat action on promoter our results support the idea that, in the case of the galectin-3 gene, Sp1-binding sequences are necessary for Tat transactivation of cellular promoter.


Figure 1. Galectin-3 expression in pNAF (a, b) or pSV2luc (c, d) transfected A549 cell line: 48h after transfection, cells were fixed, permeabilized, incubated with antibodies, washed, incubated with fluorochrome-conjugated secondary antibodies, and analyzed by confocal microscopy: (a) mouse anti HIV-1 Tat monoclonal antibodies and goat anti-mouse lissamine rhodamine antibodies; (c) rabbit anti-luciferase polyclonal antibodies and goat anti-rabbit rhodamine antibodies; (b, d) crude supernatant of the M3/38 rat hybridoma and rabbit anti-rat fluorescein antibodies.


Figure 2. Galectin-3 expression in pNAF-transfected U937 cell line. Cells were treated in the same way as in Figure 1. (a) Phase-contrast image; (b) and (c) laser-assisted confocal fluorescence images using mouse anti HIV-1 Tat monoclonal antibodies (b) or with a crude supernatant of the M3/38 rat hybridoma (c).


Figure 3. Schematic representation of the galectin-3/GFP hybrid constructions introduced in pEGFP-1 leading to pG3-204, pG3-208, and pG3-210 plasmids. Stars localize Sp1-binding site clusters.


Figure 4. GFP expression in pNAF/pG3-210 co-transfected A549 cells. Cells were treated in the same way as in Figure 1. (a) Phase-contrast image; (b) and(c) laser-assisted confocal fluorescence images using mouse anti HIV-1 Tat monoclonal antibodies (b) or directly analyzed for GFP fluorescence (c).

The fact that the upregulation of the galectin-3 expression occurs in Tat-expressing cells suggests that the expression of this protein can be induced by viral infection. Of interest is the previous observation by Schröder et al. (1995) that the expression of galectin-3 mRNA greatly increases upon infection of Molt-3 cells with HIV-1, concomitantly with the onset of expression of the viral regulatory gene tat, and thereafter declines. The increase in galectin-3 mRNA level resulted in an enhanced synthesis of galectin-3.

Moreover, it has been reported that galectin-3 promoter was significantly upregulated by expression vectors encoding the 40 kDa Tax protein, a potent transactivator in HTLV-1 (Hsu et al. 1996). Analysis of various Tax mutants suggested that galectin-3 promoter induction is dependent on activation of the cyclic-AMP-responsive element binding protein (CREB) and, to a lesser extent, NF-[kappa]B induction. 3T3 cells transformed with the Kirsten murine sarcoma virus expressed much higher levels of galectin-3 when compared with uninfected cells (Moutsatsos et al., 1987). Induction of galectin-3 expression by viral influence is likely to be significant because existing information on galectin-3 suggests that expression of galectin-3 in some cells may in fact contribute to the transformed phenotype in tumor cells (Raz et al., 1990; Hébert and Monsigny, 1994, Hébert et al., 1996). Galectin-3 expression may be closely related to cell growth. As HIV-1 Tat protein stimulates growth of cells derived from Kaposi's sarcoma (Ensoli et al., 1990) and of cytokine-stimulated endothelial cells (Mantovani et al., 1992), it is possible that elevated expression of galectin-3 is linked with this proliferative response. The beneficial role of galectin-3 to tumor cell growth suggests that expression of this lectin may indeed contribute to the pathogenesis in individuals infected with HIV.

Materials and methods

Cell culture

Adherent A549 human non small cell lung carcinoma cells (ATCC CCL 185, ATCC, Rockville, MD) and Rb-1 rabbit smooth muscle cells (Nachtigal et al., 1989) were cultured in DMEM (Gibco, Renfreshire, UK) containing 2 mM glutamine, 10% heat-inactivated fetal bovine serum FBS (Dutscher, Brumath, France), and antibiotics (100 U/ml penicillin, 100 mg/ml streptomycin). Nonadherent human promonocytic lymphoma U937 cells (ATCC CRL 1593) were cultured in OPTI-MEM medium (Gibco) supplemented with 3% heat-inactivated FBS. Cells were grown at 37°C in a humidified atmosphere containing 5% CO2.

Restriction and modification enzymes

All enzymes were purchased from Eurogentec (Seraing, Belgium) and used according to the specifications provided by the supplier.

Vectors

The vectors used were pNAF (Ventura et al., 1994) for HIV-1 Tat expression under the control of HIV-LTR and pSV2luc (Brasier et al., 1989) for luciferase expression under the control of SV40 early promoter.

The PG3-204, 208, and 210 vectors were constructed for reporter assays as follows. The fragment containing about 4.5 kb of the 5[prime]-flanking regions of the rabbit galectin-3 gene restricted in its 3[prime] part by 55 bp from the first exon was excised from pG3.5 (Gaudin et al., 1997) by a partial digestion with BamHI and a total digestion with EcoRI. This fragment was introduced into the corresponding sites of pEGFP-1 (Clontech, Palo Alto, CA) in a direct orientation with respect to the GFP reporter gene. The plasmid was designated pG3-204.

The plasmid pG3-208 was obtained by insertion into pEGFP-1, in a direct orientation with respect to the GFP reporter gene, of the BamHI/EcoRI fragment excised from p22E35 (Gaudin et al., 1997). This plasmid extends up to 8 kb upstream of the gene but lacks 2.5 kb of the 5[prime]-flanking regions of the rabbit galectin-3 gene. It is used as negative control.

The plasmid PG3-210 containing 10.5 kb upstream of the galectin-3 gene, was obtained by insertion into pG3-208 of the BamHI fragment isolated from pG3.5. The correct orientation of the fragment was verified by enzymatic digestion.

After transformation of E.coli DH5[alpha] (Gibco/BRL, Gaithersburg, MD), the plasmids were extracted according to Birnboim and Doly (1979) and purified by centrifugation in cesium chloride gradient (Radloff et al., 1967).

Transfection experiments

Adherent cells were plated in wells at 5 × 104/400 µl on 1 cm diameter glass coverslip 1 day before transfection and transfected using 2 µg of DNA in serum-free medium containing 0.6 mM polyethylenimine (PEI). After 2 h incubation at 37°C, DNA-PEI complexes were removed and cells were further cultured in serum-containing medium for 48 h.

Actively dividing U937 cells were suspended at 7 × 106/250 µl in serum-free medium. Ten micrograms of DNA were added for 5 min at room temperature before electrical discharge in a Bio-Rad Gene Pulser apparatus at 300 V and capacitance setting of 960 µF in 0.4 cm electroporation cuvette. The cuvettes were transferred to an ice bath for 15 min immediately after transfection. Cells were then cultured in 4 ml of serum-containing medium for 48 h.

Immunocytochemistry and confocal microscopy

At 48 h posttransfection, cells were washed with phosphate-buffered saline (PBS) pH 7.8, fixed with 3.7% paraformaldehyde in PBS for 15 min at room temperature (RT), and permeabilized with 0.2% Triton X-100 in PBS for 10 min at RT. Cells were washed in PBS containing 1% bovine serum albumin (PBS-BSA) and incubated with primary antibodies in PBS-BSA for 1 h at RT. The mouse anti-HIV-1 Tat monoclonal antibody (Intracel, Cambridge, MA) was used at 4 µg/ml. The rabbit anti-luciferase polyclonal antibody (Promega, Madison, WI) was used at a 1:300 dilution. Galectin-3 was detected using culture medium of the M3/38 hybridoma (ATCC TIB 166) secreting a monoclonal rat IgG against mouse galectin-3. Cells were washed three times in PBS and incubated with fluorochrome-conjugated secondary antibodies in PBS-BSA for 45 min at RT. The goat anti-mouse lissamine rhodamine (LRSC) and the goat anti-rabbit rhodamine (TRITC) conjugates (Jackson ImmunoResearch, West Grove, PA) were diluted at 1:100. The rabbit anti-rat fluorescein (FITC) antibody (Sigma, St. Louis, MO) was used at a 1:1000 dilution. Cells were washed extensively with PBS and mounted onto glass slides in a PBS/glycerol mixture containing 1% diazacyclooctane (DABCO, Sigma).

The prepared slides were examined with a confocal imaging system (MRC-1024, Bio-Rad, UK) equipped with a Nikon Optiphot epifluorescence microscope (Nikon, Tokyo, Japan) and a 60× Planapo objective (numerical aperture 1.4). The krypton/argon laser was tuned to produce both a 488 nm and a 568 nm excitation wavelength beams. Pictures were recorded with a Kalman filter (average of 10 images). Photos were obtained using ADOBE Photoshop software (Adobe House, Edinburgh, UK).

Acknowledgments

We thank Dr. A.C.Roche for critical reading of the manuscript.

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