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Endocrinology Vol. 138, No. 12 5184-5188
Copyright © 1997 by The Endocrine Society

ARTICLES

Spot 14 Protein-Protein Interactions: Evidence for Both Homo- and Heterodimer Formation in Vivo1

Barbara A. Cunningham, Marybeth Maloney and William B. Kinlaw

Departments of Physiology (B.A.C.) and Medicine, Division of Endocrinology and Metabolism (B.A.C., M.M., W.B.K.), Dartmouth Medical School, Lebanon, New Hampshire 03756

Address all correspondence and requests for reprints to: William B. Kinlaw, M.D., 714 West Borwell Building, 1 Medical Center Drive, Lebanon, New Hampshire 03756. E-mail: william.b.kinlaw.iii{at}hitchcock.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 References
 
Spot 14 (S14) is a nuclear protein that is abundant only in lipogenic tissues (liver, adipose, lactating mammary), where its expression is rapidly regulated by hormones and dietary constituents. We recently showed that S14 acts at the transcriptional level in the transduction of signals for increased expression of genes encoding lipogenic enzymes. To better understand the mechanism of the regulation of gene transcription by S14, we employed a yeast two-hybrid system to identify hepatic proteins that physically interact with S14. We found that S14 has a strong propensity for homodimerization, as is the case for many transcription factors. Relevance of this finding to mammalian cells was established by transient cotransfection of S14 constructs bearing two different epitope tags. Glutathione-S-transferase-S14 and hemagglutinin-S14 fusions copurified from the transfected cells by glutathione-affinity chromatography, indicating their association in vivo. Analysis of S14 deletion mutants in the yeast system showed that an evolutionarily conserved hydrophobic heptad repeat (zipper) near the carboxyl terminus was necessary for homodimerization. In parallel studies, we observed a 36-kDa protein that specifically coimmunoprecipitated with S14 from extracts of radiolabeled rat hepatocytes. We propose that S14 is an acidic transcriptional activator that acts as a homodimer to modulate gene expression as a component of a tripartite complex with a 36-kDa hepatic protein.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 References
 
SPOT 14 (S14) is a small (17-kDa), acidic (pI 4.9) protein that is abundant only in liver, white and brown fat, and lactating mammary gland (1, 2). Multifaceted regulation and nuclear localization of S14 prompted our hypothesis that it could function in the tissue-specific control of metabolism in response to a changing dietary and hormonal milieu. In liver, levels of S14 and its messenger RNA (mRNA) rise rapidly in response to physiological stimuli associated with the transition from the fasted to the fed state, such as dietary carbohydrate, insulin, and T3 (3). Conversely, S14 expression is curtailed in response to fasting, thyroid hormone deficiency, glucagon administration, or polyunsaturated fat feeding (4, 5, 6). Moreover, the zonal distribution of S14 expression in rat liver was limited to the perivenous portion of the liver acinus, as was that of the lipogenic enzymes (7). Such tissue-specific and diet- and hormone-dependent regulation is typical of that of the lipogenic enzymes. The S14 polypeptide sequence, however, is not similar to that of any known enzyme (8), and immunohistochemical analysis of rat liver showed that S14 was primarily nuclear in location, in contrast to the cytoplasmic locale of fatty acid synthesis (9).

Studies employing primary cultures of rat hepatocytes, treated with an antisense oligonucleotide that specifically inhibits the induction of S14 expression, supported the hypothesis that it participated in metabolic regulation (10). Antisense-treated cells showed a diminished rate of long-chain fatty acid synthesis, and this was associated with reduced cellular content of key lipogenic enzymes, including fatty acid synthase and ATP-citrate lyase. Effects of antisense-mediated S14 knockout on expression of lipogenic enzymes were mediated at the pretranslational level (11). Moreover, quantitation of other mRNAs that are induced during the fasted-to-fed transition also showed dependence on S14 expression, indicating a broader role for the protein in metabolic adaptation. Reduced activity of the glucose-inducible pyruvate kinase gene promoter in antisense-treated cells further indicated that S14 functioned at the level of transcription. These experiments established the participation of S14 in metabolic regulation at the level of the cell nucleus.

To better understand the mechanism of S14 action, we undertook studies to define interactions of S14 with hepatic proteins. We found that S14 exists as a homodimer and that dimerization depends on a carboxyl-terminal zipper domain. We also observed coimmunoprecipitation of S14 and a 36-kDa protein from rat liver, indicating the existence of a tripartite (S14-S14-p36) complex. Our data prompt the hypothesis that S14 homodimers function as an acidic transcriptional activator (12, 13), linking generic transcription factors adhering to the promoter regions of genes encoding lipogenic enzymes to tissue-specific signals for increased lipid synthesis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 References
 
Yeast two-hybrid system
Components were from Clontech (Palo Alto, CA), unless otherwise indicated. Saccharomyces cervesiae HF7c yeast were transformed with a plasmid (pGBT9) containing a full-length BglII/PstI fragment of a modified full-length rat S14 complementary DNA (cDNA) (described in Ref.8) ligated into BamHI/PstI cut vector to produce an in-frame Gal4 DNA-binding domain (DB)-S14 fusion; and the pGAD10 plasmid, containing a rat hepatic cDNA library, fused to the Gal4 transcriptional activation domain (AD). Doubly-transformed yeast were selected by auxotrophy for leucine and tryptophan, and potential positive clones were identified by auxotrophy for histidine and expression of ß-galactosidase activity. Library plasmids were isolated by their complementation of defective leucine biosynthesis in HB101 bacteria transformed with crude yeast DNA preparations. False positives were eliminated by manipulations described in the Results section. Library inserts were characterized by automated sequencing (Perkin-Elmer Applied Biosystems, Norwalk, CT) or by filter hybridization (14) with a full-length rat S14 cDNA probe.

S14 Mutants
Deletion mutations, flanked by appropriate restriction sites, were produced by PCR using a full-length rat cDNA ligated into the BglII and EcoRI sites of pSP72 (Promega, Madison, WI) as template. Primer pairs employed, and their characteristics are listed in Table 1Go. PCR products were cloned into pCRII (Invitrogen, San Diego, CA), and the mutations were confirmed by sequencing before subcloning into pGBT9 for yeast expression.


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  		Table 1. Primers used to generate mutant S14 polypeptides

 
Mammalian expression of epitope-tagged S14 polypeptides
S14 cDNAs, cloned in the appropriate reading frame into either the pCGN (15) or pEBG (16) vectors, produced S14 polypeptides fused to hemagglutinin (HA) or glutathione-S-transferase (GST) sequences, respectively, at the S14 amino terminus. Plasmids were transfected into COS 7 cells by calcium phosphate coprecipitation (9.2 µg DNA/60-mm culture dish). After approximately 60 h, cellular extracts were prepared with lysis buffer (Promega) containing 2 mM phenylmethylsulfonyl fluoride, 0.2 mg/ml leupeptin, and 50 µg/ml aprotinin, adsorbed to glutathione agarose, and eluted from the washed beads with SDS. Eluates were analyzed by Western blot using affinity-purified IgG directed against a bacterially-expressed rat S14-GST fusion protein, as described (8).

Hepatocyte culture and immunoprecipitation
Collagenase perfusion of livers from male Sprague-Dawley rats (Charles River, Cambridge, MA), weighing approximately 150 g and maintained on a 12-h photoperiod (lights on at 0700 h) with free access to normal chow (Ralston Purina, St. Louis, MO), was as previously described (10). Cells were plated in positively charged plastic dishes (143 x 103 cells/cm2) in serum-free modified William’s E medium containing penicillin, streptomycin, 5.5 mM glucose, and no linoleic acid (GIBCO-BRL, Gaithersburg, MD). Media were changed to contain 27.5 mM glucose and 50 nM T3 the following morning and again 24 h later. Cells were then incubated in methionine/cysteine-deficient medium and a mixture of 200 µCi/ml (2.0 ml/35-mm plate) 35-[S]-labeled methionine and cysteine (translabel, ICN; 12.27 mCi/ml), washed, and extracted with 200 µl lysis buffer (150 mM NaCl, 1% NP-40, 0.5% deoxycholate, 0.1% SDS, 50 mM Tris, pH 7.5) on ice x 20 min. Some cells were subjected to in vivo chemical cross-linking before extraction by the addition of 30 µl dithiobissuccinimidyl propionate (Pierce, 100 mg/ml in dimethylsulfoxide) directly to the culture medium for 30 min. Other plates received dimethylsulfoxide only. Extracts were centrifuged at 10,000 x g for 10 min and the supernatants stored at 4 C. Equal trichloroacetic acid-precipitable radioactivity (4 x 106 cpm) was added to each immunoprecipitation, which consisted of 20 µl affinity-purified rabbit anti-GST-rat S14 IgG (8), 2 mM phenylmethylsulfonylfluoride in 500 µl PBS, containing either 0.25 mg nonrecombinant GST or GST-S14 fusion protein, for 2 h at 4 C. After centrifugation, the supernatants were incubated with 200 µl (1:10 dilution) formaldehyde-pickled staphylococci (Pansorbin Cells, Calbiochem, San Diego, CA) for 15 min. The pellet was washed twice with PBS and extracted in 80 µl SDS-PAGE sample buffer (1% SDS, 5% ß-mercaptoethanol, 50 mM Tris, pH 6.8). Samples were boiled for 5 min to reverse the dithiobissuccinimidyl propionate cross-link. SDS-PAGE, electrotransfer, and autoradiography were as described (1).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
References
 
We employed a yeast two-hybrid system to screen a euthyroid rat liver cDNA library for proteins that interacted with a full-length rat S14 polypeptide bait (Fig. 1AGo). Analysis of 7.5 x 106 doubly recombinant yeast yielded 80 colonies positive for expression of the two reporter genes (histidine auxotrophy, ß-galactosidase activity). Library-derived plasmids, isolated from 10 randomly chosen potential positive clones, were evaluated to assure that they met the follow-ing 3 criteria (17): 1) they reconstituted the his+/ß-gal+ phenotype when reintroduced into yeast harboring the pGBT9-S14 bait plasmid; 2) they did not activate reporter expression in the absence of the bait plasmid; and 3) they did not activate the reporter genes when cotransfected with an irrelevant bait.



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  		Figure 1. S14 protein forms homodimers in a yeast two-hybrid system. A, The rat S14 polypeptide deduced from the sequence reported in Ref. 8. Individual residues are designated by the single-letter code. The domain designated acidic includes 13 E residues; the dimerization domain exhibits a predicted {alpha}-helical configuration (18) containing a conserved hydrophobic zipper motif. B, A typical set of ß-galactosidase filter assays of transformed yeast is shown. Columns labeled "bait" and "prey" indicate which DNA-DB- and transcriptional AD-containing plasmids were used in each case, respectively. The various combinations of plasmids employed for transformation correspond to filter-lifts numbered 1–5 and 8, as indicated along the left side of the filter: 1) S14 bait alone (Gal-4 DB-S14), full-length rat S14 sequence fused to the Gal-4 DNA-DB; 2) S14 bait and a candidate library clone (Gal-4 AD-S14, a typical S14cDNA-containing plasmid isolated from a rat hepatic cDNA library); 3) the candidate library clone alone; 4) an irrelevant bait containing a p53 tumor suppressor cDNA fused to the Gal-4 DB (Gal-4 DB-p53) and the candidate library clone; 5) irrelevant bait alone; and 6) in each set of assays, transformation with a single plasmid encoding the complete Gal-4 transcription factor cDNA (pCL1, Clontech), served as a positive control for ß-galactosidase gene activation.

 
Figure 1BGo shows typical results of ß-galactosidase filter assays of transformed yeast. The columns labeled "bait" and "prey" indicate which DNA-DB- and transcriptional AD-containing plasmids were used in each case, respectively. As shown, only in yeast cotransformed with both the candidate clone (Gal-4 AD-S14) and the S14 bait (Gal-4 DB-S14), was ß-galactosidase activity (manifest by darkening of the filter) observed. Yeast transformed with the bait plasmid alone or the candidate clone, either alone or with an irrelevant bait (p53 tumor suppressor; Gal-4 DB-p53), demonstrated no detectable ß-galactosidase activity. In each set of assays, transformation of yeast with a single plasmid encoding the full-length Gal-4 transcription factor cDNA served as a positive control for ß-galactosidase gene activation (shown as the last transformation condition in Fig. 1BGo).

Clones fulfilling criteria 1–3, detailed above, yielded nearly full-length S14 coding sequence in all 10 cases. Analysis of the 70 remaining positive clones, by dot hybridization with a rat S14 cDNA probe, indicated that they also contained S14 cDNAs. Thus, S14 has a marked capacity to homodimerize. The sequenced clones were all nearly full length. None lacked more sequence than that encoding the first 10 residues of the polypeptide, indicating that the amino terminus is not important for homodimerization.

To determine if S14 formed homodimers in mammalian cells, we transfected COS 7 cells, which do not express any detectable S14, with mammalian expression plasmids containing a nearly full-length rat S14 cDNA sequence (residues 8–150) fused to either HA-S14 or GST-S14 (Fig. 2Go). Both plasmids conferred a high level of expression of the expected fusion protein on Western blot. Analysis of cellular extracts, purified by glutathione-agarose-affinity chromatography, revealed proteins corresponding to both the GST- and HA-tagged S14 fusions (lane 4), whereas the HA-tagged protein was not detected in lysates of HA-S14-transfected cells to which exogenous GST was added before bead purification (lane 2). Therefore, S14 formed homodimers in mammalian cells. In some experiments, we detected a trace amount of nonspecific HA-S14 immunoreactivity in lysates of cells transformed with HA-S14 and the empty GST vector (lane 3). This signal was always much less than that seen when both tagged constructs were introduced together (lane 4).



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  		Figure 2. Epitope-tagged S14 polypeptides form homodimers in mammalian cells. Two separate epitope-tagged constructs, HA-S14 and glutathione S-transferase (GST)-S14, were made by ligating the rat S14 cDNA into the HA-containing pCGN and the GST-containing pEBG vectors in the proper reading frame to produce the respective fusions. COS-7 cells were transiently transfected with the HA- and/or GST-tagged S14 constructs, and purified lysates were analyzed by Western blot using an affinity-purified IgG preparation raised against a bacterially expressed GST-S14 fusion protein that contained both anti-S14 and anti-GST antibodies. Glutathione-agarose-purified lysates were prepared from cells transfected with the following constructs: lane 1, nontransfected cells; lane 2, bacterially-produced GST was added to a lysate prepared from HA-S14-transfected cells before Glutathione-bead purification; lane 3, cells transfected with both the nonrecombinant-GST and HA-S14 vectors; lane 4, cells transfected with the GST-S14 and HA-S14 vectors; lane 5, GST protein standard incubated with glutathione-agarose beads and eluted in an identical protocol as that used on the cellular lysates; lanes 6 and 8, standards added directly to the electrophoresis without bead purification (GST and hyperthyroid rat liver, respectively); lane 7, molecular mass markers (2.9–44 kDa).

 
We used S14 deletion mutants in the yeast two-hybrid system to identify sequences important for S14 homodimerization. Conway (18) recently described a cDNA, from zebra fish embryo, that showed strong sequence homology with the carboxyl-terminal region of human and rat S14. Of particular interest was the finding of a predicted leucine zipper in that portion of the zebra fish product. In the rat sequence, two of the four leucines comprising the zipper are replaced with other hydrophobic residues. We hypothesized that the hydrophobic heptad repeat could function as a dimerization domain. S14 mutants containing only residues 1–115 [S14 (1–115), therefore lacking the heptad repeat], residues 111–150 [S14 (111–150), therefore containing only the heptad repeat], and residues 66–150 [S14 (66–150), containing the heptad repeat and adjacent acidic domain] were fused to the Gal-4 DNA binding sequence, and assayed for their ability to induce ß-galactosidase activity in yeast already harboring a plasmid containing the Gal-4 transcriptional AD fused to a cDNA coding for full-length rat S14. Both filter-lift (data not shown) and quantitative liquid phase ß-galactosidase assays were performed (Table 2Go). Deletion of the hydrophobic heptad repeat abolished the interaction. The zipper region alone, however, did not confer interaction. Therefore, this conserved region was necessary, but not sufficient, to confer S14 homodimerization in yeast. Inclusion of both the midmolecule acidic region and the zipper domain of S14 in the fusion also did not reproduce the interaction, indicating that the residues between positions 10 and 66, as well as the zipper, were required for S14 homodimerization. The strength of the S14-S14 interaction was highlighted by comparing the signal generated by S14 homodimerization with that observed in yeast transfected with a construct coding for the complete Gal-4 transcription factor (see legend to Table 2Go).


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  		Table 2. Quantitative assessment of S14 homodimerization in yeast

 
S14 could interact with other hepatic proteins, and these interactions may occur exclusively with S14 homodimers. Such tripartite interactions may not be detectable in the yeast two-hybrid system. We therefore undertook studies to see whether other proteins coimmunoprecipitated with S14 from extracts of metabolically labeled primary hepatocyte cultures. An approximately 36-kDa protein (p36) specifically immunoprecipitated with S14 from extracts prepared in lysis buffer (Fig. 3Go). The interaction was stabilized by in vivo chemical cross-linking but was observed in uncross-linked cells, as well. Enhanced recovery of p36, after cross-linking, militated against an artifactual in vitro association. p36 was not found in immunoprecipitates from extracts prepared with 1% nonidet P40 (data not shown), indicating that it is not present in the soluble or membranous subcellular fractions but could be associated with the cytoskeleton, nuclear matrix, or chromatin (19). Our previous immunohistochemical observation of nuclear localization of S14 in rat liver supports the latter two possibilities over the former (8, 9). We propose that S14 exists as a homodimer in vivo that interacts with p36 to form a tripartite complex within the nucleus to modulate gene expression in lipogenic tissues. In contrast to the relatively weak association of the S14 homodimer with p36, p36 is tightly associated with a relatively insoluble nuclear substructure, such as chromatin or the nuclear matrix.



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  		Figure 3. A 36-kDa protein specifically coimmunoprecipitates with S14 from extracts of metabolically labeled rat hepatocytes in primary culture. An autoradiogram, prepared from an SDS-polyacrylamide gel of immunoprecipitated proteins, is shown. Hepatocytes were labeled with a mixture of (35)-S-methionine and cysteine, and protein extracts were immunoprecipitated with IgG directed against a bacterially expressed GST-rat S14 fusion protein (anti-FP). Immunoprecipitation was performed in the presence of excess unlabeled fusion protein (FP) or nonrecombinant GST (GST). Cultures represented in lanes 3 and 4 were chemically cross-linked in vivo before extraction. The cross-link was reversed before electrophoresis. S14, S14 protein; p36, a 36-kDa protein that specifically coimmunoprecipitated with S14 without (lane 2) or with (lane 4) cross-linking.

 


   Footnotes
 
1 This work was supported by NIH Grant DK-43142 (to W.B.K.). Back

Received June 26, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 References
 

  1. Kinlaw WB, Ling NC, Oppenheimer JH 1989 Identification of rat S14 protein and comparison of its regulation with that of mRNA S14 employing synthetic peptide antisera. J Biol Chem 264:19779–19783[Abstract/Free Full Text]
  2. Freake HC, Oppenheimer JH 1987 Stimulation of S14 mRNA and lipogenesis in brown fat by hypothyroidism, cold exposure and cafeteria feeding: evidence supporting a general role for S14 in lipogenesis in the maintenance of thermogenesis. Proc Natl Acad Sci USA 84:3070–3074[Abstract/Free Full Text]
  3. Jump D, Oppenheimer J 1985 High basal expression and 3,5,3'-triiodothyronine regulation of messenger RNA S14 in lipogenic tissues. Endocrinology 117:2259–2266[Abstract]
  4. Carr FE, Bingham C, Oppenheimer JH, Kistner C, Mariash CN 1984 Quantitative investigation of hepatic genomic response to hormonal and pathophysiological stimuli by multivariate analysis of two-dimensional mRNA activity profiles. Proc Natl Acad Sci USA 81:974–978[Abstract/Free Full Text]
  5. Kinlaw WB, Schwartz HL, Towle HC, Oppenheimer JH 1986 Opposing effects of glucagon and triiodothyronine on hepatic levels of messenger ribonucleic acid S14 and the dependence of such effects on circadian factors. J Clin Invest 78:1091–1096
  6. Jump DB, Clarke SD, MacDougald O, Thelen A 1993 Polyunsaturated fatty acids inhibit S14 gene transcription in rat liver and hepatocytes. Proc Natl Acad Sci USA 90:8454–8458[Abstract/Free Full Text]
  7. Kinlaw WB, Tron P, Witters LA 1993 Thyroid hormone and dietary carbohydrate induce different hepatic zonation of both "spot 14" and acetyl CoA-carboxylase: a novel mechanism of coregulation. Endocrinology 133:645–650[Abstract]
  8. Liaw C, Towle HC 1984 Characterization of a thyroid hormone-responsive gene from rat. J Biol Chem 259:7253–7260[Abstract/Free Full Text]
  9. Kinlaw WB, Tron P, Friedmann AS 1992 Nuclear localization and hepatic zonation of rat "spot 14" protein: immunohistochemical investigation employing anti-fusion protein antibodies. Endocrinology 131:3120–3122[Abstract]
  10. Kinlaw W, Church J, Harmon J, Mariash C 1995 Direct evidence for a role of the "spot 14" protein in the regulation of lipid synthesis. J Biol Chem 270:16615–16618[Abstract/Free Full Text]
  11. Brown SB, Maloney M, Kinlaw WB 1997 "Spot 14" protein functions at the pretranslational level in the regulation of hepatic metabolism by thyroid hormone and glucose. J Biol Chem 272:2163–2166[Abstract/Free Full Text]
  12. Lin Y, Carey M, Ptashne M, Green M 1988 Gal4 derivatives function alone and synergistically with mammalian activators in vitro. Cell 54:659–664[CrossRef][Medline]
  13. Lin Y, Green M 1991 Mechanism of action of an acidic transcriptional activator in vitro. Cell 64:971–981[CrossRef][Medline]
  14. Patterson T, Stark G, Sazer S 1995 A strategy for quickly identifying all unique two-hybrid or library plasmids within a pool of yeast transformants. Nucleic Acids Res 23:4222–4223[Free Full Text]
  15. Gimona M, Watakabe A, Helfman D 1995 Specificity of dimer formation of tropomyosins: influence of alternatively spliced exons on homodimer and heterodimer assembly. Proc Natl Acad Sci USA 92:9776–9780[Abstract/Free Full Text]
  16. Dyck J, Gao G, Widmer J, Stapleton D, Fernandez S, Kemp B, Witters L 1996 Regulation of 5'-AMP-activated protein kinase activity by the noncatalytic beta and gamma subunits. J Biol Chem 271:17798–17803[Abstract/Free Full Text]
  17. Bartel P, Chien C, Sternglanz R, Fields S 1993 Elimination of false positives that arise in using the two-hybrid system. Biotechniques 14:920–924[Medline]
  18. Conway G 1995 A novel gene expressed during zebra fish gastrulation identified by differential RNA display. Mech Dev 52:383–391[CrossRef][Medline]
  19. Staufenbiel M, Deppert W 1984 Preparation of nuclear matrices from cultured cells: subfractionation of nuclei in situ. J Cell Biol 98:1886–1894[Abstract/Free Full Text]



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