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J. Biol. Chem., Vol. 279, Issue 32, 33051-33056, August 6, 2004

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An RNA-binding Domain in the Thyroid Hormone Receptor Enhances Transcriptional Activation^*

Bin Xu and Ronald J. Koenig

From the Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0678

Received for publication, May 4, 2004

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 
Thyroid hormone plays important roles in development, differentiation, and metabolic homeostasis by binding to nuclear thyroid hormone receptors, which regulate target gene expression by interacting with DNA response elements and coregulatory proteins. We show that thyroid hormone receptors also are single-stranded RNA binding proteins and that this binding is functionally significant. By using a series of deletion mutants, a novel RNA-binding domain was localized to a 41-amino acid segment of thyroid hormone receptor 1 between the second zinc finger and the ligand-binding domain. This RNA-binding domain was necessary and sufficient for thyroid hormone receptor binding to the steroid receptor RNA activator (SRA). Although SRA does not bind directly to steroid receptors, it has been identified as a steroid receptor coactivator, and was thought not to be a coactivator for thyroid hormone receptors. However, transfection studies revealed that SRA enhances thyroid hormone induction of appropriate reporter genes and that the thyroid hormone receptor RNA-binding domain is important for this enhancement. We conclude that thyroid hormone receptors bind RNA through a novel domain and that the interaction of this domain with SRA, and perhaps other RNAs, enhances thyroid hormone receptor function.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 
Thyroid hormone 3,5,3'-triiodo-L-thyronine (T3)¹ plays important roles in development, differentiation, and metabolic homeostasis. T3 action is mediated by thyroid hormone receptors (TRs), which belong to the nuclear receptor superfamily that includes receptors for steroids, retinoids, vitamin D, and numerous other ligands (1). Based upon similarities in structure and function, nuclear receptors can be divided into functional domains designated as A-E/F, which include a divergent N-terminal A/B domain that often contains a transcriptional activation function, a well conserved DNA-binding domain (C domain), a hinge region (D domain), and the C-terminal E/F domain that binds the ligand and interacts with various corepressor or coactivator proteins. TRs are encoded by two genes, Thra and Thrb, that produce several proteins through the use of alternate promoters and/or alternative splicing. The major functional TRs are denoted TR1 and TR1. These proteins are highly conserved in sequence but are expressed at different levels in various organs and have distinct biological functions (2).

The ability to bind specific T3 response elements (TREs) in target genes is crucial for TR function. TRs bind to DNA constitutively, even in the absence of ligand, as heterodimers with retinoid X receptors (RXRs) (3) or possibly as homodimers (4, 5) or monomers (5, 6). TRs regulate gene expression essentially by functioning as scaffolding proteins; they serve as a nidus for the formation of protein complexes at the target promoter, which then regulate transcription. In the absence of T3, the conformation of the TR is such that it generally attracts a corepressor complex that has histone deacetylase activity (7, 8). In the presence of T3, the corepressor complex is released, and various coactivator complexes can be recruited. It is unclear how many distinct coactivator complexes exist or how many are required for T3 induction of gene expression, but the number of coactivator proteins identified is large and growing. A major coactivator complex contains histone acetyltransferase (HAT) and protein methyltransferase activities (9). This complex includes the steroid receptor coactivator family of p160 proteins, SRC-1 (10), SRC-2/TIF2/GRIP1 (11), and SRC-3/pCIP/ACTR/AIB1/TRAM1/RAC3 (12). The p160 proteins bind to other coactivators and also possess HAT activity, which serves to loosen chromatin structure and facilitate protein-DNA interactions (13, 14). A second coactivator complex, known as DRIP/TRAP, probably binds to the ligand-occupied receptor after the HAT complex. Numerous other coactivators have been described, and exactly where and when they function in transcriptional regulation is unclear. Steroid receptor RNA activator (SRA) is a steroid receptor coactivator that does not bind directly to steroid receptors, but probably functions as part of a complex with p160 proteins (15). Although most nuclear receptor coactivators are quite promiscuous in their action, SRA has been considered to be a specific steroid receptor coactivator, not a TR coactivator. The most intriguing aspect of SRA is that it seems to function as an RNA.

Herein we demonstrate that TRs are RNA-binding proteins. A novel RNA-binding domain was identified distal to the TR zinc fingers and proximal to the ligand-binding domain. TRs bind SRA in vitro and in cells, and SRA functions as a TR coactivator by interaction with this novel TR RNA-binding domain.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 
Plasmids and Proteins—Full-length mouse TR1 (16) and rat TR1 (17) were expressed in Escherichia coli as glutathione S-transferase (GST) fusion proteins using the vector pGEX-KG (18). To maximize the recovery of full-length proteins, the constructs were further tagged with six histidines at their C termini (GST-TR1-His6 or GST-TR1-His6), and the empty vector also encoded 6 histidines subsequent to GST. For simplicity, we refer to these proteins as GST, GST-TR1, etc. TR1 deletion mutants were constructed by inverse PCR and are described in Fig. 1. All mutations were verified by sequencing. E. coli strain BL21 carrying the fusion protein expression vectors were induced with 0.1 mM isopropyl--D-thiogalactopyranoside for 3 h at 30 °C. To increase the solubility of the receptor fusion proteins, the E. coli also contained a plasmid expressing thioredoxin (19), and the cells were lysed by French press (20). The cell lysates were applied to TALON resin (Clontech), and the hexahistidine-containing proteins were purified according to the vendor's protocol, except that 5 mM 2-mercaptoethanol was added to the buffers. The eluted proteins were further incubated with glutathione beads for 2 h. After washing three times with cold phosphate-buffered saline and once with 50 mM Tris (pH 8.0), 150 mM NaCl, 2.5 mM CaCl₂, and 2 mM dithiothreitol, the agarose beads were resuspended in 1 volume of the latter buffer with 10% glycerol and stored at -80 °C. An aliquot of the beads was boiled in SDS sample buffer and run on an SDS-polyacrylamide gel to confirm that the correctly sized protein was made and to allow adjustment to equal quantities of each of the recombinant GST fusion proteins.

View larger version (19K): [in this window] [in a new window]   FIG. 1. Schematic presentation of TR proteins. TR1, full-length TR1. Functional domains are indicated as N-terminal domain (AB), DNA-binding domain (DBD), hinge region (unlabeled region immediately following the DBD), and ligand-binding domain (LBD). The protein contains 461 amino acids. TR1, full-length TR1. The DBD is subdivided into the zinc fingers (amino acids 50-110), a region containing the T region (111-127), and a region containing the A helix (128-151). The protein contains 410 amino acids. TR1LBD, TR1 ligand-binding domain (amino acids 162-410); TRLBD, TR1 without the ligand-binding domain; TRABDN, TR N-terminal fragment terminating immediately after the second zinc finger; TRDBDC, the 51 amino acids immediately carboxyl terminal to the zinc fingers (the first 41 residues include the T region and A helix of the DBD, and the last 10 residues are the hinge region); TRC1, the 17 amino acids immediately after the zinc fingers that include the T region; TRC2, the 24 amino acids immediately following TRC1 that include the A helix; TRC3, hinge region (10 amino acids) of TR; TRC1C2, regions C1 and C2 combined; TRC2C3, regions C2 and C3 combined; TR1C1, TR1 with region C1 deleted; TR1C2, TR1 with region C2 deleted; TR1C1C2, TR1 with regions C1 and C2 deleted.

In Vitro RNA-binding Assay—Purified GST and the GST-TR proteins were adjusted to 1 µg of protein per 30 µl of beads by dilution with empty glutathione agarose beads. For each assay, 6 µl of the diluted beads were incubated with 200,000 cpm of a [³²P]RNA probe in binding buffer (10 mM Tris, pH 8.0, 2.5 mM MgCl₂, 100 mM NaCl, 0.5% Triton X-100, 2.5 mM dithiothreitol, RNase inhibitor (Roche Applied Science), and 0.5 µg of bovine serum albumin/µl) for 40 min at 4 °C with gentle rocking. The [³²P]RNA probe was made by in vitro transcription using T3 or T7 RNA polymerase and [-³²P]UTP either from pBluescript KS(+) or pSCT-SRA that had been linearized by digestion with PvuII. After incubation, the beads were washed 4x with 100 µl of binding buffer, resuspended in 50 µl of RNase-free water, and transferred to scintillation vials for determination of radioactivity in a Beckman LS2800 liquid scintillation analyzer.

Coimmunoprecipitation Assay and RT-PCR Analysis—CV-1 cells in 60-mm Petri dishes were transfected with either 6 µg of empty FLAG vector, FLAG-TR1, or FLAG-TR1 using LipofectAMINE/Plus according to the vendor's protocol (Invitrogen). Cells were harvested 48 h post-transfection, and nuclear extracts were isolated using the reagent NE-PER (Pierce). The nuclear extracts were incubated with anti-FLAG M2 agarose (Sigma) at 4 °C for 2 h. After extensive washing, the coimmunoprecipitated RNA was analyzed for SRA by RT-PCR. The RT-PCRs were performed by using a Qiagen one-step RT-PCR kit and the following conditions: 30 min at 50 °C, 15 min at 95 °C; 45 cycles of 1 min at 95 °C, 1 min at 60 °C, and 1 min at 72 °C; and a final step of 10 min at 72 °C. Products were visualized on 1.4% agarose gels by ethidium bromide staining. The SRA-specific primers used for RT-PCR were SRA RT-F, 5'-CGC GGC TGG AAC GAC CCG CCG C-3', and SRA RT-R, 5'-TAG GAG ATG GTG TCC GGT GAG TCT G-3'.

Cell Culture and Transfection Assay—CV-1 cells were maintained in minimum essential media supplemented with 10% fetal bovine serum and 2 mM L-glutamine at 37 °C and 5% CO₂. For transfection experiments, cells were split in 24-well plates 16 h before transfection and were grown in media with 10% charcoal-stripped fetal bovine serum. All transfections were performed using LipofectAMINE/Plus reagents. CV-1 cells were cotransfected with pCDM, pCDM-TR1, pCDM-TR1, or pCDM-TR1C2; TRE-Luc; pRL-TK Renilla luciferase vector (Promega); and pSCT-SRA or empty pSCT (doses are described subsequently). After transfection, cells were cultured with or without 100 nM T3. Cell lysates were harvested 48 h later for analysis of firefly and Renilla luciferases with the Promega dual luciferase reporter assay system. Renilla luciferase was used to normalize for transfection efficiency.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 
TRs Bind to RNA through a Novel RNA-binding Domain—Because RNA-binding proteins commonly bind RNA with relatively low specificity, screening assays for RNA binding often utilize probes of arbitrary sequence (23). Therefore, we developed an RNA-binding assay in which purified GST fusion proteins adsorbed to glutathione agarose beads were incubated with a ³²P-labeled 240-nucleotide RNA probe transcribed from PvuII-linearized pBluescript KS(+) with T3 polymerase. By using this assay, 35% of the input RNA probe bound to GST-TR1 (Fig. 2, bar 2), which was 10- to 20-fold greater than the amount that bound to GST (bar 1).

View larger version (26K): [in this window] [in a new window]   FIG. 2. Localization of the RNA-binding domain within TR1. Full-length or truncated GST-TR proteins (or GST as a negative control) bound to glutathione agarose beads were incubated with 200,000 cpm of a 32P-labeled RNA probe made by transcribing the pBluescript KS(+) polylinker with T3 RNA polymerase. After extensive washing, the bound counts/min were determined. The proteins are defined in Fig. 1. The assay was performed in duplicate, and the results are representative of at least three experiments. Bars indicate standard deviations.

In contrast to steroid receptors, the DNA-binding domain of TRs contains an extension carboxyl terminal to the zinc fingers. This extension includes previously described regions known as the T region and A helix (24, 25), and these lie within the DBDC fragment (Fig. 3). Therefore, we subdivided DBDC into three smaller fragments, denoted C1 (amino acids 111-127), C2 (amino acids 128-151) or C3 (amino acids 152-161). C1 contains the T region, C2 contains the A helix, and C3 contains the hinge region that separates the DBD from the ligand-binding domain. None of these fragments was capable of binding RNA (Fig. 2, bars 7-9). This led us to test the somewhat larger fragments C1C2 (amino acids 111-151) and C2C3 (amino acids 128-161), which revealed that C1C2 has full RNA-binding activity (Fig. 2, bar 10), but C2C3 does not bind RNA (bar 11). To confirm the assignment of C1C2 as the RNA-binding domain, we removed C1, C2, or C1C2 from intact TR1 and tested these deletion mutants for RNA binding. The results indicate that TR1C1 has 75% of wild-type RNA binding (Fig. 2, bar 12), TR1C2 has 25% (bar 13), and TR1C1C2 does not bind RNA (bar 14). These data confirm that C1C2 (amino acids 111-151) accounts for the RNA-binding activity of TR1.

View larger version (15K): [in this window] [in a new window]   FIG. 3. Location of RNA-binding domain C1C2 within TR1. Schematic drawing of the TR1 DBD and hinge regions, showing the two zinc fingers and the regions C1, C2, and C3, which are subdivisions of DBDC. Based upon the crystal structure of an RXR DBD-TR DBDDNA complex (25), C1 encompasses the T region and C2 matches the A helix.

RNA-binding Specificity of TR1—RNA-binding proteins commonly bind different RNA homopolymers with different binding specificities (26). Therefore, we tested the ability of non-radiolabeled poly(U), poly(C), poly(G), or poly(A) to compete with the radiolabeled RNA probe for binding to TR1 (Fig. 4). The data indicate that all of the homopolymers except poly(A) compete well. We took advantage of these data to test whether TR1 prefers to bind single-versus double-stranded RNA. We found that annealing poly(A) to poly(U) destroyed the ability of poly(U) to compete with the [³²P]RNA probe, but mixing poly(A) with poly(G) had no effect upon competition by poly(G) (data not shown). These results suggest that TR1 prefers to bind single-stranded RNA.

View larger version (16K): [in this window] [in a new window]   FIG. 4. RNA-binding specificity of TR1. RNA binding was conducted as described in Fig. 2, except that graded doses of non-radiolabeled RNA homopolymers poly(A), (G), (C), or (U) were added as competitors. Results are representative of at least two experiments.

View larger version (22K): [in this window] [in a new window]   FIG. 5. TR1 and TR1 bind to steroid receptor RNA activator. A, TRs bind to SRA in vitro. RNA binding was conducted as described in Fig. 2, except that [32P]SRA was used as the RNA probe. The assay was performed in duplicate; results are representative of at least three experiments. Bars indicate standard deviations. B, TRs interact with SRA in intact cells. CV-1 cells were transfected with empty FLAG vector, FLAG-TR1, or FLAG-TR1. Nuclear extracts were prepared 48 h later and were immunoprecipitated with anti-FLAG agarose beads. After extensive washing, the coimmunoprecipitates were analyzed by RT-PCR with SRA-specific primers. The positive control lane is a PCR using the SRA vector pSCT-SRA as template. The expected product is 680 bp. The additional band at 490 bp is discussed under "Results."

View larger version (15K): [in this window] [in a new window]   FIG. 6. SRA functions as a T3-dependent coactivator for TR1 and TR1. A, CV-1 cells were transfected with 10 ng of pCDM-TR1, pCDM-TR1, or empty pCDM; 0.5 µg of pSCT-SRA or empty pSCT; 0.25 µg of the T3-responsive luciferase plasmid 8DR4-Luc, and 10 ng of pRL-TK Renilla luciferase vector as an internal control. The transfected cells were treated with 100 nM T3 for 24 h before luciferase assay. The assay was performed in duplicate; the results are representative of at least three experiments. Bars indicate standard deviations. B, similar to A, except that the T3-responsive reporter plasmid is 2xPal-Luc.

View larger version (14K): [in this window] [in a new window]   FIG. 7. SRA function as a T3-dependent coactivator is dependent upon the TR RNA-binding domain C1C2. CV-1 cells were transfected with 30 ng of empty pCDM, pCDM-TR1, or pCDMTR1C2, 1000 ng of empty pSCT or pSCT-SRA, 250 ng of 8DR4-Luc, and 10 ng of pRL-TK Renilla luciferase vector. The cells were treated with 100 nM T3 for 24 h before luciferase assay. The assay was performed in duplicate; results are representative of at least three experiments. Bars indicate standard deviations.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The A helix, which corresponds to our region C2, may be the most critical component of the C1C2 RNA-binding domain. Although C2 by itself is not capable of binding RNA, deletion of C2 resulted in the loss of 75% of RNA binding in TR1 (Figs. 2 and 5A). In contrast, deletion of C1 resulted in the loss of only 25% of RNA binding. Interestingly, all-helical structures have also been found in various other RNA-binding domains (27). Therefore, we speculate that the -helical nature of the A helix and possibly its charged character are critical for RNA binding of TR. In addition, we speculate that other nuclear receptors that contain A helix sequences also might be RNA-binding proteins. It is interesting to compare the sequence of the TR RNA-binding domain with the RNA-binding motifs of other RNA-binding proteins, such as SR, DEAD box, and ribonucleoproteinsS. There is no obvious strong sequence homology between C1C2 and these other proteins. However, C1C2 does appear to share some homology with DEAD box proteins, especially the DEAD box subfamily p72 and p68 (Fig. 8; Ref. 28). DEAD box proteins comprise a large family of RNA-binding proteins, some of which have helicase activity. They participate in many cellular events, including transcription, RNA splicing, nuclear export of RNA, translation, and RNA degradation (29). DEAD box proteins contain six short conserved motifs, but otherwise share very little sequence conservation. The limited homology between C1C2 and p68/p72 is most apparent around motif II, which classically participates in ATP binding but not substrate RNA binding. The significance of this homology is unclear. However, it is interesting to note that the p68/p72 proteins participate in transcriptional regulation; more specifically, they interact with estrogen receptor , p160 coactivators, and SRA to enhance gene activation by estrogen (28). Thus, there is a functional similarity between these DEAD box proteins and the TR C1C2 domain.

View larger version (7K): [in this window] [in a new window]   FIG. 8. Homology between the TR1 RNA-binding domain and the DEAD box protein p72. The TR1 RNA-binding domain C1C2 was aligned with the DEAD box RNA-binding protein p72 using the ClustalW function of MacVector. The area of homology extends from p72 amino acid 214 through 298, as shown. *, amino acid identities; ^, similarities. The DEAD box motifs Ib, II, and III in p72 are indicated. Amino acids 214-298 of p72 share 98% identity with p68. Only two residues differ, and they are not among the regions of homology with C1C2 (data not shown).

As is typical of many RNA-binding proteins (23, 29), in vitro binding studies indicate that TRs bind RNA in a relatively promiscuous manner. Thus, homopolymers of poly(C), (U), or (G) all compete with the [³²P]RNA probe, although poly(A) does not. An important question is how to resolve these data with the presumed need for TRs (or other RNA-binding proteins) to bind specific RNA molecules. Perhaps the RNA-binding specificity of TRs is controlled primarily by their location within the cell and the overall protein context of the TR ribonucleoprotein complex. However, it is possible that subtle preferences for binding to specific RNA sequences become important in vivo. The selection and characterization of RNAs that bind TRs with high affinity from a random sequence RNA pool could shed light on this question. In addition, it is plausible that TRs have important functional interactions with RNAs other than SRA. For example, although TRs are almost entirely nuclear, they do shuttle between the cytoplasm and nucleus (30), and nucleocytoplasmic shuttling proteins include hnRNPs and other RNA-binding proteins (31). In addition, the TR primary transcript is subject to alternative splicing, and it is interesting to consider that TR proteins might regulate TR RNA splicing as part of a ribonucleoprotein spliceosome complex.

	FOOTNOTES

 
^* This work was supported by National Institutes of Health Grant DK44155 and the Molecular Biology Core of the Michigan Diabetes Research and Training Center, which is funded by National Institutes of Health Grant P60 DK20572. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: University of Michigan Medical Center, 5560 MSRB-II, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0678. Tel.: 734-763-3056; Fax: 734-936-6684; E-mail: rkoenig{at}umich.edu.

¹ The abbreviations used are: T3, 3,5,3'-triiodo-L-thyronine; TR, thyroid hormone receptor; SRA, steroid receptor RNA activator; GST, glutathione S-transferase; DBDC, DNA-binding domain C.

	ACKNOWLEDGMENTS

 
We thank Drs. Rainer B. Lanz and Bert W. O'Malley for kindly providing the pSCT-SRA and empty pSCT plasmids.

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TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

 

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