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At least 19 recordsLinked to original sources
PubMed1996

Restriction fragment length polymorphism in amplification products of the bovine butyrophilin gene: assignment of bovine butyrophilin to bovine chromosome 23.

A polymorphism was identified in the bovine butyrophilin (BTN) gene by digesting polymerase chain reaction products with the restriction enzyme HaeIII. This polymorphism was segregating in a Holstein-Friesian sire selected as part of an ongoing study directed towards the identification of quantitative trait loci affecting milk composition. Screening of a half-sib family established for the heterozygous sire allowed the localization of BTN to bovine chromosome 23 (BTA23).

Animals↗
PubMed1993

A review of the molecular and cellular biology of butyrophilin, the major protein of bovine milk fat globule membrane.

The molecular and cellular biology of the milk protein butyrophilin is reviewed. Butyrophilin constitutes more than 40% by weight of the total protein associated with the fat globule membrane of bovine milk. Closely related proteins are abundant in the fat globule membranes of many other species. Butyrophilin is synthesized as a peptide of 526 amino acids with an amino-terminal hydrophobic signal sequence of 26 amino acids, which is cleaved before secretion in association with the fat globule membrane. Hydropathy analysis and in vitro translation of butyrophilin mRNA indicate that the protein associates with membranes in a type I orientation via a single stretch of 27 hydrophobic amino acids in the approximate middle of the sequence. Evidence that butyrophilin is incorporated into fat globule membrane as a transmembrane protein and as a cytoplasmically oriented peripheral component is discussed. The carboxy-terminal sequence of butyrophilin is significantly homologous to two other proteins: ret finger protein and the 52-kDa nuclear antigen A of Sjögren's syndrome. Expression of bovine butyrophilin mRNA correlates with the onset of milk fat secretion toward the end of pregnancy and is maintained throughout lactation. The possible function of butyrophilin in the secretion of milk lipid droplets is discussed.

Amino Acid Sequence↗
PubMed1990

Cloning and analysis of cDNA encoding bovine butyrophilin, an apical glycoprotein expressed in mammary tissue and secreted in association with the milk-fat globule membrane during lactation.

Butyrophilin is a glycoprotein expressed on the apical surfaces of secretory cells in lactating mammary tissue, which may function in the secretion of milk-fat droplets (Franke, W. W., Heid, H. W., Grund, C., Winter, S., Freudenstein, C., Schmid, E., Jarasch, E.-D., and Keenan, T. W. (1981) J. Cell Biol. 89, 485-494). A cDNA clone encoding bovine butyrophilin was isolated and the primary structure of the protein deduced from the DNA sequence. Bovine butyrophilin contains 526 amino acids with a putative signal peptide of 26 amino acids. Hydropathy analysis predicts the existence of a single membrane-spanning region with the amino terminus facing the exoplasmic space. Butyrophilin cDNA hybridized to mRNA of 2.9 kilobases in bovine mammary tissue taken from pregnant or lactating animals, but specific mRNA was not detected in a 2-year-old virgin cow. The amount of message was maximal in lactating tissue. Butyrophilin mRNA could not be detected in bovine heart, intestine, kidney, liver, ovary, or uterus. A search of the GenBank and EMBL data banks showed closest homology was between the C termini of butyrophilin and "ret finger protein" (Takahashi, M., Inaguma, Y., Hiai, H., and Hirose, F. (1988) Mol. Cell. Biol. 8, 1853-1856). The ret-finger protein gene is expressed in a variety of tumor cell lines, mouse testis and embryonic tissue, which like the mammary gland undergo periods of rapid cell division and development. The possible significance of this homology and the possible function of butyrophilin in milk-lipid secretion are discussed.

Amino Acid Sequence↗
PubMed2006

Butyrophilin controls milk fat globule secretion.

The molecular mechanism underlying milk fat globule secretion in mammary epithelial cells ostensibly involves the formation of complexes between plasma membrane butyrophilin and cytosolic xanthine oxidoreductase. These complexes bind adipophilin in the phospholipid monolayer of milk secretory granules, the precursors of milk fat globules, enveloping the nascent fat globules in a layer of plasma membrane and pinching them off the cell. However, using freeze-fracture immunocytochemistry, we find these proteins in locations other than those previously inferred. Significantly, butyrophilin in the residual plasma membrane of the fat globule envelope is concentrated in a network of ridges that are tightly apposed to the monolayer derived from the secretory granule, and the ridges coincide with butyrophilin labeling in the globule monolayer. Therefore, we propose that milk fat globule secretion is controlled by interactions between plasma membrane butyrophilin and butyrophilin in the secretory granule phospholipid monolayer rather than binding of butyrophilin-xanthine oxidoreductase complexes to secretory granule adipophilin.

Antibodies↗
PubMed1998

Butyrophilin is expressed in mammary epithelial cells from a single-sized messenger RNA as a type I membrane glycoprotein.

We investigated the expression of butyrophilin in eukaryotic cells with a view to determining the number of mRNA species, the incorporation of the peptide chain into microsomes, and the topology of the processed protein in biological membranes. Butyrophilin is synthesized from a single sized mRNA in both bovine and murine lactating mammary tissue and associates with microsomal membranes with a type I topology (Nexo.Ccyto) via a single hydrophobic anchor in the middle of the sequence. Several isoelectric variants of the protein were detected in cellular membranes from lactating bovine mammary tissue and in the milk-fat-globule membrane. We found no evidence for soluble forms of butyrophilin in postmicrosomal supernatants. The 66-kDa protein appears to be subjected to limited proteolysis, giving rise to a 62-kDa fragment lacking the C terminus and to other more minor fragments of lower Mr in the milk-fat-globule membrane. Antipeptide antibodies to epitopes within the N- and C-terminal domains were used to show that butyrophilin retains a type I topology in plasma membranes when expressed in insect cells from a baculovirus vector, and in secreted milk-fat globules. These data do not agree with previous suggestions that butyrophilin may exist in cytoplasmic soluble forms, or be reorganized in the plane of the lipid bilayer during secretion in lipid droplets from mammary cells. The results are discussed with reference to the role butyrophilin may play as the principal scaffold for the assembly of a complex with xanthine oxidase and other proteins that functions in the budding and release of milk-fat globules from the apical surface during lactation.

Animals↗
PubMed1989

Butyrophilin of milk lipid globule membrane contains N-linked carbohydrates and cross-links with xanthine oxidase.

1. N-glycanase, but not O-glycanase, released carbohydrates from butyrophilin of rat and cow milk lipid globule membranes. 2. 1-Deoxynojirimycin, and inhibitor of glucosidases I and II of the glycoprotein processing pathway, increased the amount or extent of glycosylation of butyrophilin in rat milk lipid globules. 3. Butyrophilin and xanthine oxidase of milk lipid globule membrane had a nearest neighbor relationship, as demonstrated through specific crosslinking of these proteins. 4. From these results it is suggested that butyrophilin has asparagine-linked oligosaccharides which bypass the processing apparatus of endoplasmic reticulum and Golgi apparatus. Butyrophilin may be responsible for anchoring xanthine oxidase to the inner (cytoplasmic) face of milk lipid globule membrane.

1-Deoxynojirimycin↗
PubMed2000

BTL-II: a polymorphic locus with homology to the butyrophilin gene family, located at the border of the major histocompatibility complex class II and class III regions in human and mouse.

Comparison of human and mouse genomic sequence at the border of the major histocompatibility complex (MHC) class II and class III regions revealed a locus encoding six exons with homology to the butyrophilin gene family and the location of a previously described gene, testis-specific basic protein (TSBP). We named the new locus BTL-II, for butyrophilin-like MHC class II associated. The six discernable exons of the BTL-II locus encode a small hydrophobic amino acid sequence (which may be a signal peptide), two immunoglobulin domains, a small 7-amino acid, heptad repeat-like exon, and a further two immunoglobulin domains. In mouse, an additional butyrophilin-like gene (NG10) is situated adjacent to BTL-II. Expression studies of the BTL-II locus in mouse showed that it is expressed in a range of gut tissues. We demonstrate that like many other genes from the MHC, BTL-II is polymorphic in a selection of diverse HLA haplotypes. In the light of the newly discovered locus, we revisit and discuss the possible origin of the butyrophilin gene family.

Amino Acid Sequence↗
PubMed1996

Structural organization and mammary-specific expression of the butyrophilin gene.

Butyrophilin is a glycoprotein of the immunoglobulin superfamily that is secreted in association with the milk-fat-globule membrane from mammary epithelial cells. As a first step towards determining the possible function(s) of this protein in lactation, the mouse butyrophilin gene (Btn) has been cloned from a 129-ES cell genomic library. Over 14 kb of DNA was sequenced, including the entire transcriptional unit of the gene, and 4.6 kb and 1.1 kb of the 5' and 3' flanking region, respectively. In addition, the overall structure of the bovine gene (BTN) was determined by amplification of genomic DNA by the polymerase chain reaction. Both Btn and BTN comprise seven exons and six introns. The signal sequence and two immunoglobulin-like folds of the exoplasmic domain and the membrane anchor are encoded by separate exons, and the cytoplasmic domain is encoded by two short exons and a large terminal exon that also includes 3' untranslated sequence. The butyrophilin gene appears to have evolved from a subset of genes in the immunoglobulin superfamily and genes encoding the B30.2 domain, which is conserved in a family of zinc-finger proteins. Murine butyrophilin mRNA was detected specifically in the mammary gland by RNase protection analysis. Expression increased during the last half of pregnancy and was maximal during lactation. The 5' flanking region of Btn was analyzed for putative regulatory elements and is different from the promoters of other mammary-specific genes. Btn should be useful for determining the mechanisms underlying mammary-specific gene expression and potentially for the production of heterologous proteins in the milk of transgenic animals.

Animals↗
PubMed1983

Butyrophilin, an apical plasma membrane-associated glycoprotein characteristic of lactating mammary glands of diverse species.

Lipid globule membranes were isolated from human and bovine milk and from the milk of sheep, goat, pig, rat and guinea pig, and their polypeptide compositions were analyzed. The major polypeptides with molecular weights similar to that of bovine butyrophilin were separated by gel electrophoresis, isolated and characterized with respect to isoelectric point, molecular weight, immunological cross-reactivity and peptide composition after proteolytic cleavage. We show that in all species examined these proteins are similar to bovine butyrophilin in (i) their relative insolubility in buffers of low and high ionic strength and in non-denaturing detergents, (ii) the occurrence of several isoelectric variants, and (iii) patterns of peptides obtained by protease digestion. It is concluded that closely related proteins are major constituents of the cytoplasmic coat structures associated with milk lipid globule membranes of many species, and we propose the name butyrophilins for this group of proteins. Bovine and human butyrophilins are glycosylated with relatively large amounts of glucosamine, mannose, glucose and galactose but little fucose, sialic acids or galactosamine. Most if not all of the sugar residues are associated with an acetone-soluble peptide fragment of Mr 12000-16000 focusing at about pH 4.0. We suggest that this fragment contains a membrane-spanning peptide sequence and is involved in the attachment of the cytoplasmic coat to the membrane of the milk lipid globule.

Animals↗
PubMed1995

Carboxy-terminal cytoplasmic domain of mouse butyrophilin specifically associates with a 150-kDa protein of mammary epithelial cells and milk fat globule membrane.

A cDNA encoding mouse butyrophilin was obtained by reverse transcriptase-coupled polymerase chain reaction (RT-PCR) using poly (A)+ RNA from lactating mouse mammary gland as a template and screening a cDNA library with the RT-PCR-amplified fragment as a probe. DNA sequencing and computer analysis revealed that it has a rather long 3'-untranslated sequence and that the carboxy-terminal cytoplasmic domain was well conserved between mouse and bovine butyrophilins. To elucidate the biological function of butyrophilin, the cytoplasmic region expressed as fusion protein with glutathione S-transferase (GST) was purified and incubated with the cell lysate of mouse mammary epithelial cell lines, COMMA-ID and HC11. A 150-kDa protein was shown to specifically associate with the cytoplasmic domain and the protein increased in amount when the cells were treated with basal medium supplemented with lactogenic hormones such as prolactin, insulin and glucocorticoid. N-terminal amino acid sequencing indicated that the protein is xanthine dehydrogenase/oxidase which has been cloned from mouse liver. Further, the cytoplasmic domain also bound xanthine dehydrogenase/oxidase from bovine milk fat globule membrane. These results suggest that butyrophilin might be physiologically associated with xanthine dehydrogenase/oxidase and might function in a complex form in milk fat secretion.

Amino Acid Sequence↗
PubMed1997

Stage specific expression of milk fat globule membrane glycoproteins in mouse mammary gland: comparison of MFG-E8, butyrophilin, and CD36 with a major milk protein, beta-casein.

The expression of mouse milk fat globule membrane (MFGM) glycoproteins, MFG-E8, butyrophilin, CD36 was analyzed by Northern blot analyses. MFG-E8 and butyrophilin mRNAs were specifically detected in the mammary gland of lactating mice, whereas CD36 mRNA was detected in the heart and lung as well as in the mammary gland of lactating mice. The mRNAs of the three MFGM glycoproteins accumulated at mid-lactation were about 2-10-times as much as those of the early and late gestation stages, whereas beta-casein mRNA accumulation was dramatically increased; the mRNA at mid-lactation was no less than 40-times as much as that before lactation. In mouse mammary epithelial cell lines, HC11 and COMMA-1D, only a slight or almost no enhancement for the expression of MFG-E8, butyrophilin and CD36 mRNAs was induced simply by the treatment with the lactogenic hormones such as prolactin, insulin and dexamethasone, whereas the beta-casein mRNA expression was remarkably enhanced only by that treatment. Furthermore, while the beta-casein protein was constantly detected in milk throughout the lactation stage, the content of MFG-E8 and butyrophilin proteins increased during the lactation with an increase in the milk fat content. These results suggest that the stage-specific expression of milk fat globule membrane glycoproteins in mammary epithelial cells is regulated in a similar but not necessarily identical mechanism to that of a major milk protein, beta-casein.

Animals↗
PubMed2006

BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation.

B7 family members regulate T cell activation and tolerance. Although butyrophilin proteins share sequence homology with the B7 molecules, it is unclear whether they have any function in immune responses. In the present study, we characterize an MHC class II gene-linked butyrophilin family member, butyrophilin-like 2 (BTNL2), the mutation of which has been recently associated with the inflammatory autoimmune diseases sarcoidosis and myositis. Mouse BTNL2 is a type I transmembrane protein with two pairs of Ig-like domains separated by a heptad peptide sequence. BTNL2 mRNA is highly expressed in lymphoid tissues as well as in intestine. To characterize the function of BTNL2, we produced a BTNL2-Ig fusion protein. It recognized a putative receptor whose expression on B and T cells was significantly enhanced after activation. BTNL2-Ig inhibited T cell proliferation and TCR activation of NFAT, NF-kappaB, and AP-1 signaling pathways. BTNL2 is thus the first member of the butyrophilin family that regulates T cell activation, which has implications in immune diseases and immunotherapy.

Amino Acid Sequence↗
PubMed1995

Expression of the butyrophilin gene, a milk fat globule membrane protein, is associated with the expression of the alpha S1casein gene.

Previous in situ hybridization studies from our laboratory have shown that expression of certain milk protein genes, e.g. alpha-lactalbumin, is very high in most parts of the mammary glands of sheep and cattle, while in other areas containing an abundance of fat globules it is virtually zero (Molenaar et al., 1992). One possible explanation is that some areas of the mammary gland are dedicated to protein synthesis and some to fat synthesis. To check this possibility, the cRNA for butyrophilin, a milk-fat globule membrane protein, and hence a putative marker of milk fat synthesis, was used as a probe in in situ hybridization studies. The results show quite clearly that the patterns of expression for this gene are similar, cell type for cell type, as those for milk protein genes such as alpha-lactalbumin and alpha S1casein. In addition, we found that butyrophilin gene expression more closely matches that of alpha S1casein than that of alpha-lactalbumin. If it is shown in the future that butyrophilin is indeed a marker for milk fat synthesis, then these results support the current assumption that fat and protein synthesis do occur in the same cell.

Animals↗
PubMed1999

Cloning, expression analysis, and chromosomal localization of a novel butyrophilin-like receptor.

We isolated a cDNA clone which shows a similarity with human butyrophilin from a human colon mucosa cDNA library. The cDNA is 1964 bases long, with one open reading frame encoding a protein of 433 amino acids. The deduced amino acid sequence shows an overall homology of 36.5% with the human butyrophilin protein. This gene is mainly expressed in small intestine, colon, testis, and leukocytes. The chromosomal location of the gene was determined on the chromosome 5q35 region by polymerase chain reaction-based analysis with both a human/rodent monochromosomal hybrid cell panel and a radiation hybrid mapping panel.

Amino Acid Sequence↗
PubMed1985

Monoclonal antibodies prepared against PAS-I butyrophilin and GP-55 from guinea-pig milk-fat-globule membrane bind specifically to the apical pole of secretory-epithelial cells in lactating mammary tissue.

Monoclonal antibodies to the three major glycoproteins of guinea-pig milk-fat-globule membrane were isolated. The specificity of these antibodies was determined by solid-phase immunoassays and by immunoblotting and autoradiographic techniques after one- and two-dimensional gel electrophoresis. The antibodies bound to PAS-I, a sialoglycoprotein of Mr greater than or equal to 200 000 and the glycoproteins butyrophilin and GP-55, of Mr 63 000 and 55 000, respectively. Immunolocalization studies showed that all three proteins were highly concentrated in the apical pole of secretory-epithelial cells in mammary tissue during lactation. PAS-I, butyrophilin or GP-55, were not detected in either the basal cytoplasm of mammary epithelial cells or in myoepithelial cells, capillary endothelial cells or other cells found in the mammary gland. These proteins were either present in small amounts or were absent from mammary tissue taken in late pregnancy. The monoclonal antibodies characterized in this study will therefore be useful as probes for studies of the biogenesis of apical membrane proteins in mammary epithelial cells during lactation.

Animals↗
PubMed1996

Cloning and sequence analysis of human butyrophilin reveals a potential receptor function.

Human butyrophilin was cloned and sequenced from a human breast cDNA library. The derived amino acid sequence shows 84% sequence identity and identical domain arrangements with the previously reported bovine sequence. Sequence analysis reveals an immunoglobulin constant (IgC) domain that was not previously identified in the bovine sequence. The extracellular domain composition of butyrophilin suggests a cell surface receptor function.

Amino Acid Sequence↗
PubMed1995

Site-specific glycosylation of bovine butyrophilin.

Our previous studies showed that the N-linked sugar chains of most bovine glycoproteins from milk fat globule membranes (MFGM) contain the GalNAc beta 1-->4GlcNAc group [Sato et al. (1993) J. Biochem. 114, 890-900]. Since expression of the disaccharide structure is influenced by peptide sequences near the glycosylation sites [Smith and Baenziger (1992) Proc. Natl. Acad. Sci. USA 89, 329-333], the site-specificity of the N-acetylgalactosaminylated sugar chains was investigated using bovine butyrophilin, a major MFGM glycoprotein with known primary structure. Two glycopeptide fragments which contained the N-linked sugar chains linked to either Asn-55 or Asn-215 residue were obtained by digestion of the protein with Achromobacter protease I. The sugar chains released from each glycopeptide by hydrazinolysis were reduced with NaB3H4. Structural analyses of the oligosaccharides by sequential exoglycosidase digestion and methylation analysis revealed that only complex-type sugar chains with the GalNAc beta 1-->4GlcNAc structure are included in Asn-55-linked oligosaccharides, while only novel hybrid-type sugar chains detected previously in bovine MFGM glycoproteins are included in Asn-215-linked oligosaccharides. The results show that the glycosylation of butyrophilin occurs in a site-specific manner.

Amino Acid Sequence↗
PubMed2002

A proteomic approach to evaluate the butyrophilin gene family expression in human milk fat globule membrane.

Human butyrophilin (BTN) expression in milk fat globule (MFGM) was evaluated using two dimensional electrophoresis (2-DE) as the separation technique, and peptide mass mapping by matrix-assisted laser desorption/ionisation-mass spectrometry (MALDI-MS) as the identification tool. Since milk composition changes throughout lactation time, 2-DE maps in the pH range 4-7 of colostral MFGM and mature MFGM were compared, showing only slight differences in BTN spot distribution. The BTN gene family codes for seven proteins (BTN, BTN2A1, BTN2A2, BTN2A3, BTN3A1, BTN3A2, BTN3A3), their presence in human tissues has to date been evaluated only at a transcriptional level. Among 70 spots, analyzed and identified by MALDI-MS, 13 spots were identified as BTN spots and only one as a fragment of BTN2A1. BTN was present in multiple glycoforms, and two smaller BTN forms of about 45 kDa were also identified. We propose an array of BTNs on human MFGM, which could provide breast-fed infants with immune molecules during the neonatal period.

Amino Acid Sequence↗