International Immunology, Vol. 13, No. 7, 951-958,
July 2001
© 2001 Japanese Society for Immunology
Combinations of dominant-negative class II transactivator, p300 or CDK9 proteins block the expression of MHC II genes
Correspondence to: B. M. Peterlin
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Abstract |
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The class II transactivator (CIITA) regulates not only the transcription of HLA-DR, -DQ, -DP, but also invariant chain, DMA and DMB genes. A hybrid mutant CIITA protein, which contained residues from positions 302 to 1130 in CIITA fused to the enhanced green fluorescent protein (EdCIITA), inhibited the function of the wild-type protein. EdCIITA extinguished the inducible and constitutive expression of MHC II genes in epithelial cells treated with IFN-
and B lymphoblastoid cells respectively. Also, it blocked T cell activation by superantigen. This inhibition correlated with the localization of EdCIITA but not CIITA in the cytoplasm of cells. However, when EdCIITA was co-expressed with a dominant-negative form of the nucleoporin Nup214/CAN, it also accumulated in the nucleus. These data suggest that EdCIITA not only competes with the wild-type protein for the binding to MHC II promoters but sequesters a critical co-factor of CIITA in the cytoplasm. CIITA also recruits the histone acetyltransferase cAMP responsive element binding protein (CREB) binding protein and positive transcription elongation factor b (p-TEFb) for the transcription of MHC II genes. Dominant-negative p300 (DNp300) or CDK9 (DNCDK9) proteins inhibited the function of CIITA and of the DRA promoter. Thus, combinations of EdCIITA and DNp300 and/or DNCDK9 proteins extinguished the transcription of MHC II genes. They might become useful for future genetic therapeutic approaches in organ transplantation and autoimmune diseases.
Keywords: class II transactivator, CREB binding protein, dominant-negative protein, enhanced green fluorescent protein, MHC II, positive transcription elongation factor b
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Introduction |
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MHC II molecules present foreign antigens to Th cells and direct the subsequent differentiation of B cells. Their congenital absence leads to a severe combined immunodeficiency called the type II bare lymphocyte syndrome (BLS) (1). Using B lymphoblastoid cell lines and transient heterokaryon fusions, five complementation groups (A–E) of BLS were characterized. Whereas group E appears to affect a locus organizing region (2), the expression of all MHC II genes is extinguished in groups A–D. They contain mutations in genes that code for the class II transactivator (CIITA) and regulatory factor that binds to the X box (RFX), which is composed of three subunits, RFX-5, RFX-AP and RFX-ANK/B. In BLS-2 cells (group A), the CIITA gene has a short in-frame deletion which includes one of its nuclear localization signals (NLS) from positions 940 to 963 (3,4). Although CIITA contains an additional putative bipartite nuclear targeting sequence from positions 144 to 161 (5), both of which are conserved between human and murine CIITA proteins (6), this mutant CIITA protein is found in the cytoplasm and has no activity (4).
In the conserved upstream sequences (CUS) of MHC II promoters, RFX recognizes S and X boxes (7). Other proteins, which include the cAMP responsive element binding protein (CREB), nuclear factor Y (NF-Y: NF-YA, -YB and -YC) and octamer binding factor, bind to the downstream X2, Y and octamer sequences (8,9). They are critical for IFN--inducible and constitutive expression of MHC II genes. CIITA neither binds directly to DNA nor appears in electrophoretic mobility shift assays (EMSA) with proteins assembled on CUS (3). Nevertheless, subunits of RFX, NF-Y and CREB have been reported to bind to CIITA in cells (10–12). In one report, this binding depended on p33, which is an unknown protein that binds to the C-terminal leucine-rich repeats of CIITA (13).
CIITA attracts several transcription factors to its N-terminal activation domain. These include the TATA-box binding protein associated factors TAFII32 and TAFII70, histone acetyltransferase CREB binding protein (CBP/p300) and cyclin T1, which forms the positive transcription elongation factor b (P-TEFb) (14–20). Thus, the N-terminal region of CIITA integrates steps for the initiation and elongation of MHC II transcription.
Several mutant CIITA proteins function as dominant-negative proteins and inhibit the expression of MHC II genes in cells (5,21–25). To date, the best is a truncated CIITA protein, which lacks the N-terminal acidic and P/S/T-rich sequences (23). However, this dominant-negative CIITA protein could not extinguish the expression of MHC II genes (23). Moreover, its mechanism of action remained unexplained. Also, the dominant-negative forms of CBP (DNCBP) and CDK9 (DNCDK9 from P-TEFb) block the function of CIITA (15,18). They affect steps subsequent to the initiation of MHC II transcription.
In this report, we demonstrate that a mutant CIITA protein from positions 302 to 1130 (dCIITA) fused to the enhanced green fluorescence protein (EGFP: EdCIITA) could inhibit the transcription of MHC II genes better than dCIITA. Surprisingly, EdCIITA was found in the cytoplasm. Nevertheless, a dominant-negative nucleoporin Nup214/CAN protein (
CAN), which blocks nuclear export, retained EdCIITA in the nucleus, suggesting that EdCIITA can also sequester a critical co-factor of CIITA in the cytoplasm (26). In addition, dominant-negative forms of p300 (DNp300) and CDK9 (DNCDK9) inhibited the DRA promoter. Combinations of EdCIITA, DNp300 and DNCDK9 repressed the expression of MHC II genes synergistically. Thus, complementary strategies are more effective in extinguishing the expression of MHC II genes.
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Methods |
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Cell culture
HeLa and COS cells were grown in DMEM supplemented with 10% FCS and antibiotics (100 U/ml of penicillin G/100 µg/ml of streptomycine sulfate) at 37°C in 5% CO2. Jurkat and RM3 cells were grown in RPMI 1640 supplemented with 10% FCS and antibiotics described above at 37°C in 5% CO2.
Plasmids and the constructs
Either wild-type CIITA (amino acids 1–1130) or dCIITA (amino acids 302–1130 ) genes were fused with EGFP using pEGFP-C1 vector (Clontech, Palo Alto, CA), termed pECIITA and pEdCIITA respectively. Also, HA-tagged wild-type CIITA and dCIITA was subcloned into the same backbone vector as a control, termed pCIITA and pdCIITA respectively. The HA-tag sequence, 5'-TACCCATACGATGTTCCAGATTACGCTGCT-3', was inserted after first ATG of the N-terminus of CIITA cDNA in pCIITA and pECIITA. HA-tagged CIITA has similar activity with wild-type CIITA in the CAT assay (J. D. Fontes and B. M. Peterlin, unpublished data). All plasmids were regulated under the cytomegalovirus promoter. All plasmid constructs were sequenced and their expressions confirmed by Western blotting. The reporter gene, pDRASCAT, contains the DRA promoter linked with the CAT gene, which have been previously described (27). The empty plasmid vector was used as a stuffer DNA in all experiments. Plasmids coding for Tat, DNCDK9, DNp300 (a gift from K. Kelly), pcDNA3flagCIITA (a gift from J. P.-Y. Ting), pCAN (a gift from B. Cullen) and NF-AT–luciferase reporter gene have been described previously (18,22,26,28).
CAT assay, the analyses of the localization of EdCIITA, ECIITA and EGFP in the cells, and Western blotting
Effector gene, pCIITA, and reporter gene, pDRASCAT (0.25 or 0.4 µg each), were co-transfected with pdCIITA, pEdCIITA, pCAN or stuffer DNA (0.25–1.5 µg) in COS cells by lipofectamine (Life Technologies, Germantown, MD). COS cells (2x105) were incubated with 6 µl of lipofectamine with DNAs for 16 h. Cells were harvested and extracted with 200 µl of lysis buffer (0.25 M Tris–HCl, pH 7.5, 0.1% Triton X-100) 24 h after transfection. Lysates were inactivated at 65°C for 10 min, then mixed with 50 µl of counting buffer [0.2 µl of [3H]acetyl-coenzyme A (Amersham Life Science, Chicago, IL), 5 µl of 8.3 mg/ml chloramphenicol, 5 µl of 0.25 M Tris–HCl, pH 7.5]. Radioactivities were counted by scintillation counter (Beckman Instruments, Fullerton, CA). For the analyses of the localization of EdCIITA, ECIITA or EGFP, each construct was transfected in COS cells with or without CAN by lipofectamine as described above. The ratio of amounts of CAN against each plasmid DNA was 1:3. The localization of EGFP fusion proteins was analyzed 48 h after transfection by a Nikon E-800 fluorescence microscope (Nikon, Melville, NY). For the expression of EdCIITA and dCIITA, DNA or the empty plasmid vector (1 µg each) were transfected into COS cells. Proteins were immunoprecipitated with a rabbit polyclonal antibody against the C-terminus of CIITA. Western blotting was performed with the same antibody or an anti-actin antibody (clone I-19; Santa Cruz Biotechnology, Santa Cruz, CA)
IFN- treatment
HeLa cells (1x107) were transfected with pEdCIITA (20 µg) or the empty plasmid DNA (20 µg) by electroporation (BioRad electroporator; 975 µF, 300 V). DNA-transfected HeLa cells (2x105) were cultured for 24 h and then the cells were incubated with human IFN- (1000 U/ml; Boehringer Mannheim, Indianapolis, IN) for 72 h. HeLa cells were harvested and stained with appropriate antibodies, and then analyzed by FACS (Becton Dickinson, San Jose, CA).
Electroporation and superantigen assay
RM3 cells (1x107) were transfected with pCIITA (20 µg) and either pEdCIITA or the empty plasmid DNA (20 µg each) by electroporation as described above. The cells were harvested 48 h after transfection and stained with appropriate antibodies for FACS analyses. For superantigen assay, the electroporation was performed 48 h prior to co-culture. On the other hand, NF-AT–luciferase reporter gene (40 µg) was transfected in Jurkat cells (1x107) by electroporation 24 h prior to co-culture. The transfected Jurkat cells were cultured with either the transfected or untransfected RM3 in the presence or absence of Staphylococcal enterotoxin D (SED; Toxin Technology, Sarasota, FL) for 16 h. Cells were lysed and luciferase assays were performed as described previously (18).
FACS analyses
Both transfected HeLa cells and RM3 cells were stained with anti-DR (clone L243), -DQ (clone SK10) or -DP (clone B7/21) antibodies in PBS with 5% BSA/0.1% sodium azide for 20 min. Secondary staining was performed with phycoerythrin-conjugated rat anti-mouse 
antibody (clone X36) (all antibodies were purchased from Becton Dickinson, Mountain View, CA). The expressions of MHC II proteins and EdCIITA were analyzed by FACS.
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Results |
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EdCIITA prevents the activation of the DRA promoter by CIITA
To create an optimal dominant-negative CIITA protein, we relied on previously published work (5,21–25). dCIITA lacks the first 301 amino acids of CIITA, which include acidic (positions 26–137), bipartite nuclear targeting (positions 144–161) and P/S/T-rich sequences (positions 163–322) (Fig. 1
). The wild-type CIITA and dCIITA proteins were fused in-frame to the C-terminus of EGFP, and termed ECIITA and EdCIITA respectively. Next, we compared effects of these proteins on the DRA promoter. dCIITA or EdCIITA were co-expressed with CIITA, and the plasmid target, pDRASCAT, in COS cells. All transcripts coding for our proteins were transcribed from the cytomegalovirus immediate-early promoter. The inhibition of the DRA promoter was observed in a dose-dependent manner for each combination of plasmids. At a 1:1 molar ratio of co-transfected plasmids, EdCIITA repressed the DRA promoter 10-fold, and extinguished it to background levels at 1:3 and 1:6 molar ratios (Fig. 2, open circles). dCIITA was much less potent at these concentrations and never blocked the DRA promoter completely (Fig. 2, solid triangles). Although only effects at 72 h are presented, identical results were obtained at shorter and longer times after transfection (data not presented). EdCIITA could function better than dCIITA because of its different composition (the addition of EGFP), greater stability or subcellular localization. We conclude that EdCIITA is a strong dominant-negative CIITA protein. Moreover, because it is linked to EGFP, its levels of expression can be monitored easily in cells.
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) and dCIITA (
) respectively. Error bars give SEM from three experiments performed in duplicate. Below the graph are presented expression levels of EdCIITA, dCIITA and actin, which were determined by Western blotting. Lysates were immunoprecipitated with the rabbit polyclonal anti-CIITA antibody and then blotted with the same antibody. Levels of actin were determined with an anti-actin antiserum.IFN-
fails to induce the expression of MHC II genes in HeLa cells expressing EdCIITAThe administration of IFN-
activates the Jak/Stat signaling cascade and CIITA transcription (29,30). This induction is critical for the function of antigen-presenting cells. To confirm that EdCIITA could also block effects of IFN-, we expressed EdCIITA for 2 days in HeLa cells, which were subsequently treated with 1000 U/ml of IFN- for 3 days. Cells were stained with the antibody against DP and then analyzed by FACS (Fig. 3). The expression of EdCIITA was followed by green fluorescence and was abundant in ~30% of HeLa cells for the duration of the assay. In Fig. 3, they are visualized on the x-axis (Fig. 3E, R2). Cells in the R1 region did not express pEdCIITA and resembled untransfected cells (Fig. 3E). Importantly, the inhibition of DP was observed only in cells that expressed EdCIITA (Fig. 3, R2). These data were confirmed with antibodies against DR determinants (data not presented). Thus, EdCIITA also blocks the induction of MHC II genes by IFN-.
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In the presence of EdCIITA, CIITA cannot restore the expression of MHC II genes in B lymphoblastoid RM3 cells
RM3 cells were established as a MHC II-deficient B cell line from Raji cells. However, the exogenous expression of CIITA in these cells leads to the synthesis of MHC II determinants to levels that are comparable to those on parental Raji cells. We chose RM3 because of the slow decay of pre-existing MHC II–peptide complexes on Raji and other antigen-presenting cells. As presented in Fig. 4
(B), the introduction of CIITA restored high levels of expression of DR, DQ and DP determinants on RM3 cells. In sharp contrast, CIITA failed to rescue the expression of MHC II determinants in the presence of EdCIITA (Fig. 4C). This inhibition was from 9.8 to 0.9% of DR+ cells, 9.3 to 1.4% of DP+ cells and 4.0 to 0.4% of DQ+ cells respectively (Fig. 4, cf. B and C). This inhibition was observed only in green fluorescent RM3 cells that expressed EdCIITA. These results were confirmed in RJ2.2.5 cells (data not presented). Thus, EdCIITA inhibits efficiently the expression of MHC II genes in B lymphoblastoid cells.
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EdCIITA blocks the presentation of superantigen by MHC II determinants to T cells
EdCIITA blocked the expression of MHC II genes in kidney cells (COS) that expressed CIITA, IFN-
-treated epithelial cells (HeLa) and B lymphoblastoid cells (RM3). Moreover, since Ii, DMA and DMB genes are also regulated by CIITA, EdCIITA should block antigen processing and presentation. To examine functional consequences of this blockade, we studied effects of EdCIITA on T cell activation via superantigen and MHC II determinants on B cells. The diagram of this experiment is presented in Fig. 5(A). Again, RM3 cells expressed CIITA with or without EdCIITA. Transfected cells were co-cultured with Jurkat cells, which contained the NF-AT–luciferase reporter gene, in the presence or absence of SED. MHC II complex:superantigen induces T cell signaling via the TCR and activates the NF-AT reporter gene in Jurkat cells. The expression of CIITA alone resulted in NF-AT activity only in the presence of SED (Fig. 5, lane 6). On the other hand, EdCIITA strongly inhibited our superantigen assay (Fig. 5, lane 8). Levels of inhibition correlated perfectly with the expression of MHC II genes and the inhibition of the DRA promoter (Fig. 2
). Similar results were obtained when a plasmid target containing the NF-B binding sites linked to luciferase was used (data not presented). Thus, EdCIITA blocks the expression and function of MHC II determinants.
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Unlike CIITA, EdCIITA is localized in the cytoplasm
It is thought that the dominant-negative CIITA proteins, such as dCIITA, compete with CIITA for the binding to MHC II promoters in the nucleus of cells. To check the validity of this model, we examined the distribution of EdCIITA in COS cells. As presented in Fig. 6
(A), ECIITA was found in the nucleus. In sharp contrast, EdCIITA was localized in the cytoplasm (Fig. 6B). EGFP alone was distributed throughout the cell (Fig. 6C). This result suggests that EdCIITA acts indirectly to block the function of CIITA. One possibility is that it sequesters a co-factor of CIITA in the cytoplasm.
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Although mutant CIITA proteins lacking the C-terminal NLS and bearing mutations in GTP-binding domains are found in the cytoplasm, EdCIITA still contains both sequences. EdCIITA lacks only the putative N-terminal NLS (Fig. 1
). Thus, EdCIITA should still enter the nucleus. Additionally, CIITA contains many leucines, especially near its C-terminus, some of which are spaced in a manner reminiscent of nuclear export signals (NES). Thus, it is possible that EdCIITA enters the nucleus but is rapidly exported to the cytoplasm. In the steady state, EdCIITA would then appear cytoplasmic. To examine directly whether these shuttling mechanisms in EdCIITA functioned, we co-expressed the dominant-negative nucleoporin CAN, which blocks the function of NES (26). Indeed, when EdCIITA was co-expressed with CAN, EdCIITA was localized in the nucleus (Fig. 6E). On the other hand, ECIITA and EGFP retained their previous subcellular distribution (Fig. 6D and F). We conclude that CIITA is a shuttling protein, that it contains functional NLS and NES, and that EdCIITA most likely competes for the binding to MHC II promoters in the nucleus as well as sequesters a co-factor of CIITA in the cytoplasm.
DNp300, DNCDK9 and Tat also inhibit CIITA and act synergistically with EdCIITA
Previously, we demonstrated that CIITA binds to CBP and cyclin T1 from P-TEFb to affect the chromatin conformation and elongation of transcription of MHC II genes. Dominant-negative forms of CBP or p300 (DNp300, Fig. 1) and CDK9 from P-TEFb (kinase dead CDK9, CDK9N167N, DNCDK, Fig. 1) could inhibit MHC II transcription. Since Tat, which is an essential transactivator of viral replication, bound to the same surface on cyclin T1 and blocked effects of CIITA, HIV-1 inhibits efficiently antigen processing and presentation by MHC II determinants. DNp300 and DNCDK9 are nuclear proteins that act at a post-assembly step, when DNA-bound proteins have already recruited CIITA. Thus, they should block the activity of the residual CIITA in B cells and antigen-presenting cells, and act synergistically with each other and EdCIITA.
Indeed, Tat and both dominant-negative proteins potentiated effects of EdCIITA in COS cells. Tat, DNp300 and DNCDK9 alone inhibited CIITA function on the DRA promoter (Fig. 7A, lanes 4, 6 and 8). They acted synergistically with small amounts of EdCIITA (Fig. 7A, lanes 5, 7 and 9). Moreover, the combination of EdCIITA, DNp300 and DNCDK9 extinguished the expression from the DRA promoter to background levels (Fig. 7B, lane 4). All dominant proteins were expressed to equivalent levels in these cells (data not presented). We conclude that EdCIITA, DNp300 and DNCDK9 act at different steps of MHC II transcription and thus synergistically to block the function of CIITA.
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Discussion |
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In this study we demonstrated that EdCIITA inhibits efficiently the function of CIITA. EdCIITA diminished the expression of MHC II genes in HeLa cells, which were treated with IFN-
, and in B lymphoblastoid RM3 cells. EdCIITA also inhibited T cell activation by superantigen. Surprisingly, at steady state, whereas CIITA was localized in the nucleus, EdCIITA was found in the cytoplasm. However, EdCIITA is a shuttling protein. CAN blocked the export of EdCIITA from the nucleus, which suggested that EdCIITA sequesters some co-factor of CIITA in the cytoplasm. DNp300, DNCDK9 or Tat inhibited the remaining CIITA in the nucleus. Since EdCIITA, DNp300, DNCDK9 or Tat affect different steps in the transcription of MHC II genes, they acted synergistically. We conclude that combinatorial approaches might offer the best hope of extinguishing the expression of MHC II genes in cells and in the organism. This study used the most recent advances in our understanding of steps in the assembly and function of regulatory proteins on MHC II promoters. CREB, and subunits of NF-Y and RFX bind to DNA and to CIITA. However, this recruitment requires an additional protein of 33 kDa, which binds to the leucine-rich repeats in CIITA and possibly other co-factors. These other cellular proteins might explain the dichotomy between binding studies of individual components (CREB, CIITA, NF-Y and RFX) in cells and the inability of CIITA alone to bind to these proteins in EMSA. Additionally, CIITA binds to general transcription factors and CBP to initiate MHC II transcription. CIITA also binds to P-TEFb, which phosphorylates the C-terminal domain of RNA polymerase II to elongate MHC II transcription. Our dominant-negative strategies attacked these different steps.
First, EdCIITA linked dCIITA to EGFP. The latter addition facilitated expression and localization studies of this chimera. Surprisingly, EdCIITA worked better than dCIITA and was found in the cytoplasm. dCIITA is a nuclear protein and is present on MHC II promoters in chromatin immunoprecipitations (10). Since it also transits the nucleus, EdCIITA most likely competes with the wild-type protein for the binding to MHC II promoters as well as sequesters a co-factor of CIITA in the cytoplasm. It is possible that the absence of the N-terminal bipartite NLS leaves an unbalanced NES, thereby favoring export of EdCIITA. Alternatively, EGFP itself could favor the cytoplasmic localization, directly or via a conformational change in the fusion protein. Indeed, several other mutations in CIITA, which preserve the N-terminal and C-terminal NLS, keep the mutant protein in the cytoplasm. Importantly, the N-terminal NLS and none of the putative NES have been examined directly for their function.
Second, despite its competition with EdCIITA, the endogenous CIITA can still exert some effects. To this end, we also blocked the ability of CIITA to attract CBP, which remodels chromatin, and of P-TEFb to phosphorylate the C-terminal domain of RNA polymerase II. Indeed, the addition of DNp300 and DNCDK9 functioned synergistically with EdCIITA to extinguish the expression of MHC II genes. As expected, these proteins had to be added separately. A chimera between EdCIITA and DNp300, DNCDK9 or Tat alone or in combination functioned no better than EdCIITA alone. EdCIITA in the cytoplasm and DNp300 or DNCDK9 in the nucleus would then target most efficiently different cellular partners of CIITA. At these lower concentrations of separate components, we would also expect fewer deleterious effects on the transcription of other cellular genes.
The model that emerges from this study is presented in Fig. 8. Since effects of CBP and P-TEFb in MHC II transcription had already been diagrammed, only the sequestration of a critical co-factor for CIITA is depicted. In this scenario, CIITA is a shuttling protein that resides mostly in the nucleus. What circumstance would require its rapid removal from the nucleus via the NES is speculative, but could include aspects of innate immunity, sepsis or toxic shock. With the removal of the N-terminal activation domain and the addition of EGFP, EdCIITA is now a predominantly cytoplasmic protein. However, it transits the nucleus, where it could also compete for the binding to MHC II promoters and remove a critical co-factor from CIITA (protein X). This event might not only inhibit productive interactions between CIITA and MHC II promoters but also affect the communication between CIITA and the general transcriptional machinery. Further details of this mechanism require the isolation and characterization of this co-factor(s). Additionally, strategies of delivering two to three separate dominant-negative proteins efficiently and reproducibly into cells need to be addressed.
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Acknowledgments |
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We thank for Paula Zupanc-Ecimovic for excellent secretarial assistance, and members of the laboratory for help in all aspects of this work and comments on the manuscript. This work was supported by the Nora Eccles Treadwell Foundation.
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Abbreviations |
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| BLS bare lymphocyte syndrome |
| CIITA class II transactivator |
| CBP CREB binding protein |
| CUS conserved upstream sequences |
| CREB cAMP responsive element binding protein |
| EMSA electrophoretic mobility shift assay |
| EGFP enhanced green fluorescence protein |
| NES nuclear export signal |
| NF-Y nuclear factor Y |
| NLS nuclear localization signal |
| P-TEFb positive transcription elongation factor b |
| RFX regulatory factor X |
| SED streptococcal enterotoxin D |
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Notes |
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Transmitting editor: T. Sasazuki
Received 26 January 2001, accepted 13 April 2001.
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