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J. Biol. Chem., Vol. 277, Issue 4, 2463-2467, January 25, 2002

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Dual Mechanisms for Repression of the Monomeric Orphan Receptor Liver Receptor Homologous Protein-1 by the Orphan Small Heterodimer Partner^*

Yoon-Kwang Lee and David D. Moore

From the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Received for publication, June 5, 2001, and in revised form, September 7, 2001

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The orphan nuclear hormone receptor liver receptor homologous protein-1 (LRH-1; NR5A2, also known as FTF), an unusual receptor that binds DNA as a monomer, is an essential regulator of expression of a rate-limiting enzyme in bile acid formation, cholesterol 7--hydroxylase. In a classic negative feedback loop that is a crucial component of the complex regulation of cholesterol metabolism, cholesterol 7--hydroxylase expression is decreased when bile acid levels are high. This repression is thought to be based on the bile acid-dependent induction of expression of the orphan receptor small heterodimer partner (SHP) NR0B2, which inhibits the activity of LRH-1. We have explored the molecular basis for this important regulatory effect by characterizing the mechanisms by which mouse and human SHP inhibit LRH-1-mediated transactivation. Both SHP proteins specifically interact with the AF-2 transactivation domain of LRH-1 both in vivo and in vitro. This domain is a common target for coactivator interaction, and the SHP proteins can compete with p160 coactivators for binding to LRH-1. In addition to the N-terminal receptor interaction domain, SHP includes a C-terminal domain with autonomous repression function. Neither a deletion nor a point mutation specifically affecting this domain blocked the ability to interact with LRH-1 to compete for coactivator binding or to repress LRH-1 transactivation. However, the relative ability of these mutants to inhibit LRH-1-mediated transactivation was markedly decreased. We conclude that the proposed central role of SHP in cholesterol metabolism is based on a two-step mechanism that is dependent on both coactivator competition and direct transcriptional repression.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The orphan receptor SHP¹ lacks the highly conserved DNA binding present in other members of the nuclear hormone receptor superfamily (1). Although SHP does not bind DNA directly, a number of reports demonstrate that SHP can interact with a variety of nuclear hormone receptors including the thyroid hormone receptor, the retinoic acid receptor, the peroxisome proliferator-activated receptor-, the estrogen receptor-, the retinoid-X-receptor (RXR), and the orphan receptor HNF-4 (1-6). These interactions result in repression of the transcriptional activities of such SHP targets. Initial results with retinoic acid receptor-RXR heterodimers indicated that SHP can inhibit DNA binding in some cases (1). However, the identification of an autonomous repression function of SHP suggested the existence of additional repression mechanisms for SHP (3). This function could be particularly important for target receptors that bind DNA as monomers, because such receptors would not be sensitive to inhibitory processes based on disrupting dimeric complexes. More recent results have demonstrated that SHP can also inhibit transactivation by several receptors that bind DNA as homodimers, including estrogen receptor, RXR, and HNF-4 (4-6). This repression does not appear to involve effects on DNA binding and is thought to be dependent on a two-step mechanism in which SHP decreases transactivation, first by competing with p160 coactivators for binding to the nuclear receptors and second by the actions of the as yet poorly characterized autonomous SHP repression activity (3, 6).

Recent results have suggested that the orphan receptor LRH-1 is a particularly crucial target for the inhibitory effects of SHP (7, 8). LRH-1 is a liver-enriched transcription factor that is closely related to the orphan SF-1, which is essential for sexual differentiation and development of tissues in which it is expressed including adrenals and gonads (9, 10). The DNA-binding domain of LRH-1 shares over a 90% identity and 95% similarity with that of SF-1, and both bind with high affinity as monomers to a conserved core DNA motif present in the promoters of target genes (7-9, 11-14). Earlier, we reported that either SF-1 or LRH-1 could transactivate the SHP promoter, which contains several such motifs (15). The existence of a negative feedback regulation of SHP expression, at least in liver, was suggested by the observation that LRH-1 transactivation was particularly sensitive to inhibition by SHP. However, this effect may be limited to liver, because SF-1 was relatively resistant to the effects of SHP. More recent data also suggest that LRH-1 is essential for expression of the cytochrome p450 7A(CYP7A1) gene, which encodes cholesterol 7-hydroxylase, a rate-limiting enzyme in the conversion of hepatic cholesterol to bile acids (7, 8, 13). Increased levels of bile acids are thought to result in decreased CYP7A gene expression through a novel indirect feedback loop in which increased levels of bile acids stimulate SHP gene expression via activation of the bile acid receptor FXR (Farnesoid X receptor) (7, 8). In this mechanism, the functional interaction of SHP and LRH-1 is the linchpin of a central axis in cholesterol regulation.

The molecular basis for SHP inhibition of LRH-1 transactivation has not been defined. Although the mechanisms for the effects of SHP on other targets have been explored, unique aspects of the functional interaction of SHP with LRH-1 and SF-1 raise the possibility of distinct mechanisms for these proteins. Thus, the function of these two receptors as monomers suggests that their interactions with both DNA and coactivators may differ significantly from those of other receptors. This possibility is strongly supported by some unusual transactivation functions of SF-1 (16, 17), which may underlie the lack of inhibition of SF-1 by SHP. It remains uncertain whether LRH-1 transactivation is associated with such unusual mechanisms.

Prompted by both the importance of the functional interaction between SHP and LRH-1 and this uncertainty, we have characterized the mechanisms by which SHP inhibits LRH-1 transactivation. SHP did not inhibit LRH-1 DNA binding. As observed with the homodimeric receptors HNF-4, RXR, and estrogen receptor, SHP did compete with p160 coactivators for binding to LRH-1. SHP mutants, retaining the receptor interaction function but lacking the autonomous repression function due to either a deletion (mSHPW160X) (3) or a point mutation (hSHPR213C) (18), were able to inhibit LRH-1 transactivation. However, the limited extent of this repression suggests that active repression by SHP is essential for efficient LRH-1 inhibition as described for RXR and estrogen receptor. We conclude that the previously described two-step process involving both coactivator competition and direct repression is conserved in the SHP inhibition of transactivation by the monomeric orphan receptor LRH-1.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Cell Culture and Transient Transfection-- HepG2 cells were maintained in 75-cm² tissue culture flasks with Dulbecco's modified Eagle's medium plus 10% fetal bovine serum. One day before transfection, confluent cells were trypsinized and plated into 24 well plates with a 1:4 ratio to allow the cells to reach 50-60% confluency at the time of transfection. Cells were refed with fresh medium 1 h before transfection. All transfections were carried out using the calcium phosphate method with 0.2 µg/well of both the luciferase reporter and TKGH internal control plasmids and the indicated amounts of expression plasmids as described previously (6). Luciferase expression was assayed and normalized using growth hormone expression 30-36 h after transfection. All luciferase values were the mean of triplicates.

Plasmids-- All plasmids used here were described previously (6, 15) with the exception of the LRH-1C and human SHP constructs. LRH-1C was created by PCR with primers designed to remove the C-terminal AF-2 core motif of six amino acids, LLIEML. Both the VP16 and GST versions of LRH-1 and LRH-1C contain the putative ligand-binding domain of LRH-1 (amino acids 145-495). A pBluescript plasmid containing full-length human SHP was purchased from IncyteGenomics (GenBank^TM accession number t69324). A PCR-amplified insert was introduced to pCDM8, pCMXGal4, and pCMXVP16 plasmids. The hSHPR213C mutant was created using PCR. All PCR constructs were confirmed by DNA sequencing.

In Vitro Binding Assays-- The glutathione S-transferase pulldown assay was used to examine protein-protein interaction in vitro. GST alone or GST fusion proteins were expressed in Escherichia coli, and equivalent amounts were bound to glutathione-Sepharose beads (Amersham Biosciences, Inc.). Incubations with [³⁵S]methionine-labeled target proteins were run for 4 h. Unbound and nonspecifically bound proteins were removed by washing four times with a HEPES buffer, pH 7.6, containing 100 mM NaCl and 0.1% Triton X-100. Specifically bound proteins were eluted by treatment with 15 mM glutathione, subjected to SDS-PAGE, and visualized by autoradiography. The amount of specifically bound proteins was determined using a PhosphorImager.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

To initially characterize the repression of LRH-1 transcriptional activity by SHP, we used a transient transfection approach with a previously described reporter plasmid in which five SF-1-binding elements control luciferase gene expression (19). As expected from their conserved DNA-binding specificity (11), this SF-1 luciferase reporter was strongly transactivated by LRH-1 (Fig. 1A), and the coexpression of mouse SHP efficiently inhibited LRH-1-mediated transactivation in a dose-dependent manner (Fig. 1A, bars 3-5). Similar results were observed with the LRH-1-responsive SHP promoter (data not shown). This inhibition is not dependent on decreased DNA binding by LRH-1, because the addition of SHP did not affect the specific recognition of an SF-1/LRH-1 response element by LRH-1 in vitro as measured by the electrophoretic mobility shift assay (data not shown). Moreover, SHP efficiently repressed transactivation by the chimeric Gal-LRH-1, in which the Gal4 DNA-binding domain replaces that of LRH-1 (Fig. 1B). This latter repression was particularly strong. Only 5 ng of SHP expression vector completely inhibited transactivation by 20 ng of the Gal-LRH-1 vector, and 20 ng of the SHP vector decreased normalized luciferase expression to approximately <20% of the basal level observed with the reporter alone or Gal4 alone (Fig. 1B, compare bars 1 and 2 with bar 8). This net repression is consistent with previous results with RXR (6) and suggests an important function for the autonomous repression function of SHP in LRH-1 inhibition.

View larger version (13K): [in this window] [in a new window]   Fig. 1.   Repression of LRH-1-mediated transactivation by SHP. A, direct repression of LRH-1-mediated transactivation by mouse SHP. HepG2 cells were cotransfected with 200 ng of pCILRH-1, 200 ng of SF-1 luciferase (SF-1luc) reporter, 150 ng of TKGH, and the indicated amount of mouse SHP plasmid. Comparable expression of SHPW160X was confirmed by Western blotting (6). The luciferase values are the normalized means of three separate transfections. The first bar represents a normalized luciferase value from transfection with reporter alone. B, repression of Gal4LRH-1 transactivation. HepG2 cells were cotransfected with 200 ng of Gal4 or Gal4LRH-1, 200 ng of Gal4TK luciferase, 150 ng of TKGH, and the indicated amount of mouse SHP plasmid. The first bar represents transfection with reporter plasmid only. C, repression of LRH-1-mediated transactivation by human SHP. HepG2 cells were cotransfected with 100 ng of pCILRH-1, 200 ng of SF-1luc reporter, 150 ng of TKGH, and the indicated amount of human SHP plasmid.

To test this prediction, a previously characterized SHP mutant lacking the C-terminal autonomous repression domain (deletion of C-terminal amino acids 160-260), mSHPW160X, was used. This mutant also repressed transactivation by either the intact LRH-1 or Gal-LRH-1 but with significantly reduced efficiency (Fig. 1, A and B). Notably, SHPW160X failed to decrease Gal-LRH-1 transactivation below basal levels, even at higher concentrations (Fig. 1B, bar 11) (data not shown).

We also tested human SHP for repression on this context. As depicted in Fig. 1C, human SHP also robustly repressed the LRH-1-mediated transactivation (Fig. 1C, bars 3 and 4). However, this was significantly decreased by a human SHP mutation hSHPR213C previously associated with mild obesity in Japanese subjects (Fig. 1C, bars 5 and 6) (18). This finding is consistent with the decreased inhibitory effect of this mutation on HNF-4 transactivation, and with the results described below, this finding suggests that this mutation specifically affects the SHP autonomous repression domain.

Previously, we have shown that SHP specifically requires the AF-2 surface of homodimer-binding nuclear receptors for both interaction and repression (6). To test whether SHP also targets AF-2 surface of the monomeric LRH-1, a deletion of the conserved six amino acid motif of the putative helix 12 of LRH-1 was introduced in the context of a VP16 activation domain chimera. The ability of wild type VP16LRH-1 or the VP16LRH-1C to interact with Gal4-mSHP and hSHP was examined using the mammalian two-hybrid system. As shown in Fig. 2, VP16LRH-1 showed a strong interaction with both of the Gal-SHP proteins, which was completely eliminated by the AF-2 mutation in VP16LRH-1C. In agreement with these results, ³⁵S-labeled murine SHP interacted efficiently in vitro with a bacterially expressed GST-LRH-1 fusion but not with GST-LRH1C (Fig. 3A). The ability of the truncated mSHPW160X to interact with GST-LRH-1 was also assessed. This mutant retained significant binding as expected from previous results, although this was decreased somewhat (~13% retention of input of wild type SHP and 8% SHPW160X, Fig. 3A). The human mutant protein hSHPR213C was also tested for its interaction with LRH-1 using the mammalian two-hybrid system. The interaction of hSHPR213C with LRH-1 was indistinguishable from that of wild type SHP (Fig. 3B).

View larger version (10K): [in this window] [in a new window]   Fig. 2.   SHP targets the AF2 surface of LRH-1. HepG2 cells were cotransfected with 50 ng of Gal4mSHP and Gal4hSHP and 100 ng of VP16LRH-1 plasmids.

View larger version (21K): [in this window] [in a new window]   Fig. 3.   Interaction of wild type and mutant SHP with LRH-1. A, upper panel, interaction between mouse SHP or SHPW160X and LRH-1 in GST pulldown assays. GST alone and GST-LRH1 and GST-LRH1C fusion protein were expressed in E. coli, purified, bound to glutathione-Sepharose beads, and tested for interaction with [35S]methionine-labeled SHP or SHPW160X prepared by coupled in vitro transcription and translation. Bound proteins were eluted and resolved by SDS-PAGE. The same amount of loading of GST fusions was confirmed by Coomassie Blue staining. Bottom panel, the intensities of the specific bands were quantitated using a PhosphorImager. The percent retention was determined by comparison to the marked 25% input. B, interaction of human SHP or the SHP R213C mutant with LRH-1 in mammalian cells. HepG2 cells were cotransfected with 50 ng of Gal4hSHPWT or Gal4hSHPR213C, 50 ng of VP16 alone or VP16LRH-1, 200 ng of Gal4TK luciferase reporter, and 150 ng of TKGH as an internal control.

We have previously described a modified mammalian two-hybrid approach to assess the ability of a third protein to affect the interaction between two Gal4 and VP16 chimeras (6). We used this approach to test whether SHP and coactivators compete for interaction with LRH-1. A relatively strong transactivation was observed when Gal4SRC-3(RID), a chimera containing the receptor interaction domain of the p160 coactivator SRC-3 (also known as ACTR, p/CIP, RAC-3, AIB-1, TRAM-1) was coexpressed with VP16LRH-1 in HepG2 cells, indicating a strong interaction of LRH-1 with SRC-3 (Fig. 4A, bar 4 and B, bar 2). No such interaction was observed with the GalSRC-3(RID) and VP16LRH-1C, confirming that the AF-2 surface is required for this interaction (data not shown). As described previously (6), a transcriptional activation domain was incorporated into the VP16-SHP fusion used for competition to counteract the SHP expression function. Thus, the inhibitory effects observed are not a consequence of incorporation of the SHP repression function into a ternary complex. Increasing amounts of transfected VP16mSHP (Fig. 4A, bars 5-7) or VP16hSHP (Fig. 4B, bars 3 and 4) strongly decreased the LRH-1-SRC-3 interaction, indicating that SHP can compete for LRH-1 binding with SRC-3. The same result has been obtained with increasing amounts of SHP. Increasing levels of mSHPW160X also decreased this interaction, but in agreement with the biochemical results, they were less efficient than the wild type SHP. In contrast, hSHPR213C competed with SRC-3 for binding to LRH-1 as efficiently as wild type hSHP (Fig. 4B, bars 3 and 4 with bars 5 and 6), indicating that this mutation does not affect receptor binding.

View larger version (15K): [in this window] [in a new window]   Fig. 4.   Murine and human SHP compete with SRC-3 for interaction with LRH-1 in vivo. A, competition between mouse SHP and SRC-3 for binding to LRH-1 in mammalian two-hybrid assays. HepG2 cells were transfected with 100 ng of Gal4SRC-3(RID), 500 ng of VP16 or a VP16 fusion to the LRH-1 ligand-binding domain (VP16LRH-1(L)), and the indicated amounts of plasmids expressing VP16mSHP or VP16mSHPW160X. B, competition between human SHP and SRC-3 for binding to LRH-1. Transfection assays were carried out as shown in A with the exception that indicated amounts of VP16hSHP or VP16hSHPR213C were used.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The orphan nuclear receptor SHP lacks a DNA-binding domain and exerts its inhibitory effects through protein-protein interactions (1-6). The results described here demonstrate that SHP interacts directly with the orphan receptor LRH-1, which binds DNA as a monomer. These data are consistent with previous results found with other receptors and the initial descriptions of the functional interaction of the two orphan receptors (7, 8, 15). However, several considerations suggested the possibility that the interactions of these two unusual orphans might differ from those described previously for SHP. As a monomer, the interactions of LRH-1 with both DNA and coactivators must differ from those of the much larger group of receptors that function as dimers. Thus, the effects of SHP on these interactions might be expected to differ from those exerted on the dimeric receptors. This is particularly clear for SF-1, which has been shown to have unusual cofactor interactions (16) and transactivation functions (17) that may be linked to the unexpected absence of inhibitory effects of SHP. In the absence of characterization LRH-1 transactivation, the mechanisms of its inhibition by SHP remain uncertain. The fact that this inhibition has been proposed to play a crucial role in cholesterol metabolism clearly highlights the importance of defining its molecular basis.

The results described here demonstrate that SHP directly targets the AF-2 surface of LRH-1 and competes with coactivators for binding to the same surface. Once bound to the target receptor and recruited to DNA, the autonomous repression function of SHP further contributes to the overall inhibitory effect. Both of these effects are similar to those described for other receptors, and we conclude that the two-step mechanism for repression is a general feature of SHP inhibition of transactivation mediated by both dimeric and monomeric nuclear receptors.

The molecular basis for the function of the SHP repression domain remains unknown. To date, we have not been able to demonstrate significant interaction between SHP and previously identified corepressors including NCoR, SMRT, mSin3, or histone deacetylases. In addition, trichostatin A, a potent inhibitor of histone deacetylase activity, has no apparent effect on the SHP repression. Although negative, these results suggest that SHP exerts its repressive effects on target gene promoters by a mechanism distinct from those previously described for nuclear hormone receptors. It is intriguing that in this scenario the repressed state, which results from SHP binding to an activated receptor, could be quite different from that engendered by the absence of ligand for thyroid hormone receptor or retinoic acid receptor, for example.

Recently, a heterozygous loss of SHP gene function was associated with a mild form of obesity in a number of Japanese subjects (18). This finding suggests a function for SHP in metabolic regulation beyond the effects on cholesterol metabolism predicted from its effects on LRH-1 (7, 8, 15). Whereas more detailed functional studies will be required to elucidate the physiologic functions of SHP, the nature of these human gene mutations may provide some insights into SHP repression. Several of the mutations are large truncations, but three of them are point mutations that affect a relatively short span of the repression domain (amino acids 189-213). Like the more severe mutations, all of these SHP point mutants are defective in the repression of HNF-4 transactivation. As indicated by the results described here, one of the mutations (hSHPR213C) probably has a general effect on the autonomous repression function. Further characterization of the specific functional effects of these mutations may lead to insights into the mechanism of repression by SHP.

The interaction between SHP and LRH-1 shares both interesting similarities and apparent differences with the previously described interaction between DAX-1 and SF-1 (23). Based on both structural similarity and direct sequence comparisons (41% identity in the ligand-binding domains), DAX-1 is the closest relative to SHP. SF-1 and LRH-1 are even closer relatives with a 53% identity in the ligand-binding domain and 90% identity in the DNA-binding domain, accounting for their highly similar DNA-binding specificity. Both SHP and DAX-1 inhibit transactivation of their specific nuclear receptor targets, and both interact with receptor ligand-binding domains via LXXLL-related motifs similar to those present in p160 and other coactivators (20, 21). In addition, both SHP and DAX-1 harbor autonomous repression functions that are located in the C-terminal region, and mutations that specifically affect this region have been identified in human populations (3, 18, 22, 23). However, the inhibitory targets of DAX-1 appear far more restricted than those of SHP. In addition, DAX-1 has been reported to recruit corepressors such as NCoR and Alien, and DAX-1 does not require the AF-2 surface of SF-1 for interaction and repression (24, 25). Focusing further studies on these issues may either narrow the differences or highlight their functional significance.

	FOOTNOTES

^* This work was supported by National Institutes of Health Grant P01 DK57743.The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Tel.: 713-798-3313; Fax: 713-798-3017; E-mail: moore@bcm.tmc.edu.

Published, JBC Papers in Press, October 19, 2001, DOI 10.1074/jbc.M105161200

	ABBREVIATIONS

The abbreviations used are: SHP, small heterodimer partner; LRH-1, liver receptor homologous protein-1; SF-1, steroidogenic factor-1; RXR, retinoid X-receptor; HNF-4, hepatocyte nuclear factor-4; GST, glutathione S-transferase; TK, thymidine kinase; DAX, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1; SRC-3, steroid receptor coactivator-3.

	REFERENCES

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				J.-Y. Kim, H.-J. Kim, K. T. Kim, Y.-Y. Park, H.-A Seong, K. C. Park, I.-K. Lee, H. Ha, M. Shong, S. C. Park, et al. Orphan Nuclear Receptor Small Heterodimer Partner Represses Hepatocyte Nuclear Factor 3/Foxa Transactivation via Inhibition of Its DNA Binding Mol. Endocrinol., December 1, 2004; 18(12): 2880 - 2894. [Abstract] [Full Text] [PDF]

				K. Boulias and I. Talianidis Functional role of G9a-induced histone methylation in small heterodimer partner-mediated transcriptional repression Nucleic Acids Res., November 18, 2004; 32(20): 6096 - 6103. [Abstract] [Full Text] [PDF]

				J. Qin, D.-m. Gao, Q.-F. Jiang, Q. Zhou, Y.-Y. Kong, Y. Wang, and Y.-H. Xie Prospero-Related Homeobox (Prox1) Is a Corepressor of Human Liver Receptor Homolog-1 and Suppresses the Transcription of the Cholesterol 7-{alpha}-Hydroxylase Gene Mol. Endocrinol., October 1, 2004; 18(10): 2424 - 2439. [Abstract] [Full Text] [PDF]

				J. K. Kemper, H. Kim, J. Miao, S. Bhalla, and Y. Bae Role of an mSin3A-Swi/Snf Chromatin Remodeling Complex in the Feedback Repression of Bile Acid Biosynthesis by SHP Mol. Cell. Biol., September 1, 2004; 24(17): 7707 - 7719. [Abstract] [Full Text] [PDF]

				P.-L. Xu, Y.-Q. Liu, S.-F. Shan, Y.-Y. Kong, Q. Zhou, M. Li, J.-P. Ding, Y.-H. Xie, and Y. Wang Molecular Mechanism for the Potentiation of the Transcriptional Activity of Human Liver Receptor Homolog 1 by Steroid Receptor Coactivator-1 Mol. Endocrinol., August 1, 2004; 18(8): 1887 - 1905. [Abstract] [Full Text] [PDF]

				L. A. Freeman, A. Kennedy, J. Wu, S. Bark, A. T. Remaley, S. Santamarina-Fojo, and H. B. Brewer Jr. The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter J. Lipid Res., July 1, 2004; 45(7): 1197 - 1206. [Abstract] [Full Text] [PDF]