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J. Biol. Chem., Vol. 278, Issue 3, 1411-1414, January 17, 2003

This Article Abstract Full Text (PDF) All Versions of this Article: 278/3/1411    most recent C200619200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wandall, H. H. Articles by Clausen, H. Search for Related Content PubMed PubMed Citation Articles by Wandall, H. H. Articles by Clausen, H. Social Bookmarking                      What's this?

ACCELERATED PUBLICATION
Drosophila egghead Encodes a 1,4-Mannosyltransferase Predicted to Form the Immediate Precursor Glycosphingolipid Substrate for brainiac^*

Hans H. Wandall, Johannes W. Pedersen, Chaeho Park^§, Steven B. Levery^§, Sandrine Pizette^¶, Stephen M. Cohen^¶, Tilo Schwientek, and Henrik Clausen

From the  School of Dentistry, University of Copenhagen, Nørre Allé 20, 2200 Copenhagen N, Denmark, the ^§ Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, and the ^¶ European Molecular Biology Laboratory, Meyerhofstr 1, 69117 Heidelberg, Germany

Received for publication, November 5, 2002, and in revised form, November 25, 2002

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The neurogenic Drosophila genes brainiac and egghead are essential for epithelial development in the embryo and in oogenesis. Analysis of egghead and brainiac mutants has led to the suggestion that the two genes function in a common signaling pathway. Recently, brainiac was shown to encode a UDP-N-acetylglucosamine:Man1,3-N-acetylglucosaminyltransferase (3GlcNAc-transferase) tentatively assigned a key role in biosynthesis of arthroseries glycosphingolipids and forming the trihexosylceramide, GlcNAc1-3Man1-4Glc1-1Cer. In the present study we demonstrate that egghead encodes a Golgi-located GDP-mannose:Glc1,4-mannosyltransferase tentatively assigned a biosynthetic role to form the precursor arthroseries glycosphingolipid substrate for Brainiac, Man1-4Glc1-1Cer. Egghead is unique among eukaryotic gly- cosyltransferase genes in that homologous genes are limited to invertebrates, which correlates with the exclusive existence of arthroseries glycolipids in invertebrates. We propose that brainiac and egghead function in a common biosynthetic pathway and that inactivating mutations in either lead to sufficiently early termination of glycolipid biosynthesis to inactivate essential functions mediated by glycosphingolipids.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The Drosophila genes brainiac and egghead play essential roles in epithelial development in the embryo and during oogenesis (1, 2). Brainiac and egghead encode proteins that are required in the germline to allow for normal interaction between germ line and somatic cells in the developing ovary (2). In the absence of brainiac or egghead in the germ line defects are observed in the overlying follicular epithelium, which is of somatic origin (1, 2). On one hand, these follicular epithelial defects resemble defects in epidermal growth factor receptor signaling between germ line and follicle cell layers. On the other hand, they resemble a subset of the follicular defects associated with Notch mutants (1-3). Defects in female fertility have also been described (4). The diversity of defects caused by brainiac and egghead mutants suggests that they may be involved in communication between cells at a fundamental level and that they can affect multiple signaling pathways.

Brainiac and egghead mutants exhibit similar and non-additive phenotypes, leading to the proposal that they function in a common signaling pathway. Based on sequence analysis, Yuan et al. (5) originally proposed that brainiac together with the distant homologous gene fringe encoded glycosyltransferases. This hypothesis has subsequently proved correct and both represent glycosyltransferases with functionally conserved mammalian homologs (6-9). Brainiac encodes a UDP-N-acetylglucosamine:Man1,3-N-acetylglucosaminyltransferase (3GlcNAc-transferase)¹ with a predicted function in biosynthesis of arthroseries glycosphingolipids in the Drosophila (8, 9). Brainiac was shown to catalyze addition of the third monosaccharide residue to form the trihexosylceramide glycolipid, GlcNAc1-3Man1-4Glc1-1Cer. Arthroseries glycolipids have only been found in invertebrates and differ fundamentally from mammalian glycolipids by having a core disaccharide structure based on Man1-4Glc1-Cer (MacCer) rather than Gal1-4Glc1-Cer (LacCer) (10). Interestingly, brainiac was found to transfer 1-3 linked GlcNAc to both MacCer and LacCer, while mammalian homologs only transfer to LacCer (8, 9, 11). Sequence analysis of egghead indicates that it could encode a type II transmembrane glycosyltransferase. Homologous genes appear limited to invertebrates, and no similar genes are found in the mammalian databases. In the present study we tested the hypothesis that egghead encodes a unique invertebrate glycosyltransferase activity in the same biosynthetic pathway as brainiac and present evidence that egghead indeed encodes a 1,4-mannosyltransferase predicted to form the MacCer precursor glycolipid substrate for brainiac.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Expression of egghead in Insect-- An expression construct of the full coding region of egghead was prepared by reverse transcriptase-PCR using Drosophila melanogaster mRNA and the sense primer Egh001 (5'-AGCAGATCTCAAGATGAACTCCACCACAAAG-3') with a BglII restriction site and the antisense primer Egh002 (5'-AATAGTCTAGACAGTCTCCAGTACGCG-3') with a XbaI restriction site. The resulting 1.37-kb fragment was cloned into the BglII/XbaI sites of pVL1393 (PharMingen) and pVL1393-MYC. Baculovirus expression constructs, pVL-egghead-full and pVL-egghead-Myc-full, were co-transfected with Baculo-Gold^TM DNA (PharMingen) in Sf9 cells as described (12). Control constructs included pVL-GalNAc-T4-full (13) and pVL-brainiac-full (8). Standard enzyme assays were performed in 50-µl reaction mixtures containing 25 mM HEPES-KOH (pH 7.4), 10 mM MgCl₂, 0.1% n-octylgalactoside (Sigma), and 100 µM GDP-[¹⁴C]Man (2,000 cpm/nmol) (Amersham Biosciences), and varying concentration of acceptor substrates (purchased from Fluka, Merck, Sigma, and Toronto Research Chemicals Inc.; see Table I for structures). Assays with brainiac were carried out in the same reaction mixture except for addition of UDP-[¹⁴C]GlcNAc (3,000 cpm/nmol) (Amersham Biosciences) and MnCl₂. Enzyme sources were microsomal fractions of baculovirus-infected Sf9 and High Five^TM cells prepared essentially as described (14). Briefly, cells were lysed in lysis buffer (25 mM Tris-HCl (pH 7.4), 250 mM sucrose); after incubation 30 min on ice cells were homogenized and lysate centrifuged at 1,000 × g. Glycerol was added to 20%, and membrane pellets were obtained by 100,000 × g. Pellets were used at 10 mg/ml (protein concentration determined by BCA, Pierce). Reaction products of soluble acceptors were quantified by chromatography on Dowex AG1-X8 (Sigma). Assays with glycosphingolipids included 5 mM 2-acetamido-2-deoxy-D-glucono-1,5-lactone (inhibitor of hexosaminidase activity), and products were purified on octadecyl-silica cartridges (Supelco) and analyzed by high performance thin-layer chromatography followed by autoradiography.

Expression of egghead in CHO Cells-- The 1.37-kb fragment used for baculo constructs was cloned into the BamHI/XbaI sites of pcDNA3(+). CHO-K1 cells were stably transfected with the pcDNA3-egghead-Myc-full as described previously and clones selected with anti-Myc antibodies (13). Cells were grown to subconfluence and fixed with 3% paraformaldehyde and immunostained with anti-Myc monoclonal antibody (Invitrogen). Transferase assays were performed in standard reaction mixtures with cell lysates.

Isolation and Analysis of a Product Formed by egghead-- The product formed with n-octyl glucoside (1 mg) was purified on octadecyl-silica cartridges (Bakerbond, J. T. Baker), followed by stepwise elution with increasing concentrations of methanol in water. The purified glycolipid was deuterium-exchanged by repeated addition of CDCl₃-CD₃OD 2:1, sonication, and evaporation under nitrogen, then dissolved in 0.5 ml of Me₂SO-d₆, 2% D₂O (0.03% tetramethylsilane) for NMR analysis. One-dimensional ¹H, two-dimensional ¹H-¹H gCOSY, TOCSY, and ROESY NMR spectra were acquired on a Varian Inova 500 MHz spectrometer at 35 °C.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

tBLASTn searches performed with D. melanogaster egghead coding region (GenBank^TM accession number NM_080313) of the National Center for Biotechnology Information data base and the whole genome data base GadFly released by the Berkeley Drosophila Genome Project revealed genes with significant similarity in flies (diptera) and nematodes, including Caenorhabditis elegans. Low sequence similarity was found to the putative cellulose synthetase CelA (GenBank^TM accession number AAC41435) from Agrobacterium tumefaciens as well as other bacterial genes predicted to be glycosyltransferases (GenBank^TM accession numbers NP_348317 (Clostridium acetobutylicum) and NP_531181 (A. tumefaciens str. C58)). No significant similarity was found with mammalian genes. egghead is predicted to encode a protein of 457 amino acids with a putative N-terminal signal sequence and a putative hydrophobic transmembrane retention signal (3), which is typical for Golgi located glycosyltransferases. SDS-PAGE Western blot analysis with anti-Myc antibodies of lysates of baculovirus-infected High Five^TM cells or a stable CHO egghead transfectant revealed a single protein migrating with an apparent molecular weight of 52 kDa (not shown). Subcellular localization of egghead was analyzed by immunofluorescense staining of a stable CHO egghead transfectant, where immunoreactivity was limited to a supranuclear pattern characteristic for Golgi localization (not shown). A similar staining pattern was found for a stable CHO transfectant with human 3GnT2 (not shown), as well as transfectants with other human glycosyltransferases (13). The GadFly data base predicts that egghead contains a sugar nucleotide donor substrate binding site with potential DXD/E binding motifs (15).

egghead Encodes a GDP-Man:Glc1,4-Mannosyltransferase-- Initial assays of activity included a screen with high concentrations of monosaccharide substrates and different donor substrates as described previously (6, 8). Microsomal fractions of infected High Five^TM cells expressing the full coding region of egghead exhibited a marked increase in GDP-Man transferase activity with D-glucose (Fig. 1). Egghead exhibited strict donor substrate specificity for GDP-mannose and did not utilize other donor sugar nucleotides tested (UDP-Gal, UDP-GalNAc, UDP-GlcNAc). Analysis of a panel of mono- and disaccharide derivatives showed that egghead exhibits strong preference for substrates containing terminal -linked glucose (-Glc) (Table I). Interestingly, some Man monosaccharide derivatives also served as efficient substrates; however, no activity was found with the disaccharides Man1-4GlcNAc and Man1-4Glc1-n-Oct. Analysis of apparent K_m for the most active substrates identified showed that n-octyl--Glc was the preferred acceptor substrate (apparent K_m 0.67 ± 0.08 mM) with Glc1-pNph (apparent K_m 1.10 ± 0.3 mM) being comparable and Man1-pNph (apparent K_m 2.30 ± 0.5 mM) less preferred. The apparent K_m for GDP-Man with n-octyl--Glc acceptor substrate was 58.0 ± 6.2 µM.

View larger version (11K): [in this window] [in a new window]   Fig. 1.   egghead exhibits GDP-Man:Glc mannosyltransferase activity with monosaccharides. Microsomes of transfected High FiveTM cells were used as enzyme sources. Donor sugar nucleotides included GDP-Man, UDP-Glc, UDP-Gal, UDP-GlcNAc, UDP-GalNAc, UDP-Xyl. Designations are as follows: , egghead with GDP-Man and D-glucose; , control with GDP-Man and D-glucose; , egghead with GDP-Man and L-mannose; , control with GDP-Man and L-mannose; , egghead with GDP-Man and D-galactose; , control with GDP-Man and D-galactose; +, egghead with D-GlcNAc; *, control with D-GlcNAc. Control background values represented activity with microsomal fractions expressing human polypeptide GalNAc-T4.

View this table: [in this window] [in a new window]   Table I Substrate specificities of Egghead 1-4-mannosyltransferase

Optimization of the enzyme assay using microsomal membranes demonstrated that Triton X-100, Triton CF-54, and Nonidet P-40 inhibited egghead activity at 0.1%, while n-octylgalactoside at 3.4 mM (0.1%) and to a lesser extent CHAPS activated the enzyme. The pH optimum of egghead activity was pH 7-8. Addition of 5-10 mM MgCl₂ and MnCl₂ activated enzyme activity (Mg²⁺ being better than Mn²⁺), and CaCl₂ had no effect, while addition of 10 mM EDTA destroyed the activity.

Analysis of egghead activity in the established CHO transfectant cells showed the same properties as when egghead is expressed in insect cells (not shown). Attempts to visualize in vivo formed products by lectin staining with Vicia Faba (Sigma) was unsuccessful, and further characterization of the products formed await large scale production of cells for chemical analysis of glycolipids.

Egghead Functions in Glycosphingolipid Biosynthesis-- Glycosphingolipids of the fruit fly are based on the arthroseries GlcNAc1-3Man1-4Glc1-1Cer core (10). The finding that egghead exhibits -mannosyltransferase activity with Glc acceptor substrates strongly suggested that egghead transfers Man to Glc1-1Cer to form MacCer. As shown in Fig. 2 egghead utilizes Glc1-1Cer as an acceptor substrate, whereas LacCer does not serve as substrate. In addition, Gal1-1Cer was found not to serve as a substrate (not shown). Based on this result it was predicted that egghead functions as the MacCer synthase. Evidence in support hereof was provided by showing that brainiac utilizes the product formed by egghead (Fig. 3). This assay was carried out with n-octyl--Glc as initial acceptor substrate because it served as a better substrate than GlcCer under the assay conditions used.

View larger version (8K): [in this window] [in a new window]   Fig. 2.   Egghead transfer Man to Glc1-1Cer. Microsomal fraction of egghead and GalNAc-T4 were incubated with Glc1-1Cer, LacCer, or no glycolipid and GDP-Man as described under "Experimental Procedures." Autoradiography of thin-layer chromatography of reaction products (4 h) is shown. Plate was run in chloroform-methanol-water (60/38/10, v/v/v). Migration of standard glycolipids is indicated with arrows.

View larger version (30K): [in this window] [in a new window]   Fig. 3.   The product formed by egghead with n-octyl-Glc serves as a substrate for brainiac. High performance thin-layer chromatography analysis of product developments (2 h) with combinations of microsomal fractions of egghead (Egh), polypeptide GalNAc-T4 (GT4), and brainiac (Brn) expressing High FiveTM cells and combinations of sugar nucleotides GDP-Man and UDP-GlcNAc are shown. The upper panel is stained with orcinol, and the lower panel represents an autoradiography. Plates were run in chloroform-methanol-water (60/30/8, v/v/v), and the migration of n-octyl-Glc (NOG) and the disaccharide and trisaccharide products hereof are indicated in the margins. Man-Glc-Oct is formed only in the presence of egghead and GDP-Man, and GlcNAc-Man-Glc-Oct is formed only in the presence both of egghead and brainiac as well as GDP-Man and UDP-GlcNAc. In lane 7, the asterisks indicate that the autoradiography assay was carried out with non-labeled GDP-Man to confirm that the initial added sugar was Man.

Structural Characterization of Product Formed by egghead-- A one-dimensional ¹H NMR spectrum of the diglycosyl product formed with n-octyl--glucoside exhibited resonances consistent with ~55% conversion to Man1-4Glc1-1-n-octyl, i.e. anomeric signals at 4.477 and 4.143 ppm (³J_1,2 = ~1 and 7.9 Hz, respectively), corresponding to H-1 of Man1-4 and Glc1-1 residues of this glycolipid. H-1 of unreacted Glc1-1 is observed at 4.080 ppm (³J_1,2 = 7.6 Hz) (Fig. 4). Following complete assignment of ¹H resonances from all three monosaccharide spin systems present (see Table II) by two-dimensional ¹H-¹H gCOSY and TOCSY experiments (not shown), the connectivity between the -Man and the more abundant -Glc (spin system originating from the H-1 at 4.143 ppm) was established as a 14 linkage by a two-dimensional ROESY experiment, which showed a dipolar cross-relaxation correlation between -Man H-1 and -Glc H-4. This is consistent with the substantial downfield shift of H-4 compared with that observed for unreacted n-octyl -glucoside (3.350 versus 3.016). Although other -Glc resonances are affected by the glycosylation, H-4 is shifted downfield by the largest increment (_H-4 = 0.334 ppm; _H-3 = 0.244 ppm; _H-5 = 0.151 ppm).

View larger version (22K): [in this window] [in a new window]   Fig. 4.   Downfield region of 500-MHz 1H NMR spectrum (Me2SO-d6, 2% D2O, 35 °C) of the Man1-4Glc1-1-n-octyl product of egghead. Arabic numerals refer to ring protons of residues designated by standard three-letter monosaccharide nomenclature in the corresponding structure; P = product; S = substrate.

View this table: [in this window] [in a new window]   Table II 1H chemical shifts (ppm) and 3J1,2 coupling constants (Hz, in parentheses) for Glc1-n-octyl substrate and biosynthetic Man4-Glc1-n-octyl product. Data were obtained in Me2SO-d6, 2% D2O at 35 °C. Chemical shifts are referenced to internal tetramethylsilane (set to 0.000 ppm).

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The original prediction that the neurogenic genes brainiac and egghead encoded proteins serving functions in a common pathway has been verified by demonstrating that both genes encode glycosyltransferases and that egghead can synthesize the immediate precursor glycolipid substrate for brainiac. The two enzymes function very early in glycosphingolipid biosynthesis at the second and third steps in build-up of the glycan chain, and it is likely that this reflects the severe phenotypes associated with inactivation of these genes. Glycosphingolipids of Drosophila have been reported to be based on the arthroseries and exist as extended oligosaccharide structures such as Gal1-3GalNAc1-4GalNAc1-4GlcNAc1-3Man1-4Glc1-1Cer, which can be terminated by glucuronic acids and modified with phosphoethanolamine to give charged and zwitterionic glycolipids (10, 16). Specific biological functions of distinct glycolipid structures have not been elucidated in Drosophila, but it is conceivable that termination of glycolipid biosynthesis at GlcCer and at MacCer could block biological activity of glycolipids to similar effect.

Genetic approaches to studying glycosphingolipid functions in mammals have so far provided some insight into defined biological activities. In contrast to invertebrate glycolipids that appear to be based on one class, mammalian glycolipids are based on multiple classes. Mice deficient in ganglioseries glycolipids built on GalNAc1-4Gal1-4Glc1-Cer have yielded significant information (17-21). Globoseries glycolipids built on Gal1-4Gal1-4Glc1-Cer are dispensable in man as evidenced from the rare P^k and p blood groups (22, 23). While the biosynthesis of ganglioseries and globoseries glycolipids are carried out by unique single copy genes, each step in the biosynthesis of lacto- and neolactoseries glycolipids based on the fact that GlcNAc1-3Gal1-4Glc1-Cer is carried out by multiple isoenzymes, many of which serve functions in the synthesis of glycoproteins as well (24). Drosophila and C. elegans may in this respect constitute simpler systems for studies of functions of glycolipids. Recently, the 4GalNAc-transferase acting in sequence after brainiac to form GalNAc1-4GlcNAc1-3Man1-4Glc1-1Cer was characterized (25).

An increasing number of genes involved in biosynthesis of glycoconjugates have been identified as essential or important for normal development of flies and nematodes. A number of genes involved in biosynthesis of the proteoglycan core region were identified through an elegant screen for defects in vulval invagination of C. elegans (26), and these include glycosyltransferases functioning in precursor-product relationships and relevant sugar nucleotide transporters (27), fringe, a distant homolog of brainiac, was found to encode a key enzyme controlling elongation of O-linked fucose directly on Notch (6, 7), and precursor-product relationships with glycosyltransferases functioning after fringe have also been implicated (28). To our knowledge, egghead and brainiac are currently the only available examples of essential genes in Drosophila with functions in the biosynthesis of glycolipids. Glycolipids are known to serve important biological functions in mammals including modulation of receptor functions (29). Modulation may be mediated through direct lectin-carbohydrate interactions between the receptor and glycolipids (30) or through organization of lipid rafts, which are known to be enriched in MacCer in Drosophila (31). Egghead and brainiac offers new tools to decipher mechanisms of receptor modulation through glycolipids.

	FOOTNOTES

^* This work was supported by Human Science Frontier Program RGP0063/2002-C, the Velux Foundation, the Danish Medical Research Council, National Institutes of Health Resource Center for Biomedical Complex Carbohydrates Grant NIH P41 RR05351, European Community Marie Curie Fellowship IHP HPMF-CT-2000-01083, and Biological Research Infrastructure Network-Center for Structural Biology Grant NIH P20 RR16459.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 the correspondence should be addressed: School of Dentistry, Nørre Alle 20, DK-2200 Copenhagen N, Denmark. Tel.: 45-35326835; Fax: 45-35326505; E-mail: henrik.clausen@odont.ku.dk.

Published, JBC Papers in Press, November 25, 2002, DOI 10.1074/jbc.C200619200

	ABBREVIATIONS

The abbreviations used are: 3GlcNAc-transferase, UDP-N-acetylglucosamine:acceptor 1,3-N-acetylglucosaminyltransferase; Cer, ceramide; LacCer, lactosylceramide; MacCer, mactosylceramide; TOCSY, total correlation spectroscopy; gCOSY, gradient-enhanced correlation spectroscopy; ROESY, rotating frame Overhauser spectroscopy; CHO, Chinese hamster ovary; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

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This Article Abstract Full Text (PDF) All Versions of this Article: 278/3/1411    most recent C200619200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wandall, H. H. Articles by Clausen, H. Search for Related Content PubMed PubMed Citation Articles by Wandall, H. H. Articles by Clausen, H. Social Bookmarking                      What's this?