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Receptor for Mouse Hepatitis Virus Is a Member of the Carcinoembryonic Antigen Family of Glycoproteins

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Receptor for Mouse Hepatitis Virus Is a Member of the Carcinoembryonic Antigen Family of Glycoproteins Proc. Natl. Acad. Sci. USA Vol. 88, pp. 5533-5536, July 1991 Medical Sciences Receptor for mouse hepatitis virus is a member of the carcinoembryonic antigen family of glycoproteins (coronavirus/immunoglobulin superfamily/host resistance to virus/virus tissue tropism/virus receptor) RICHARD K. WILLIAMS, GUI-SEN JIANG, AND KATHRYN V. HOLMES* Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 Communicated by Dorothy M. Horstmann, April 1, 1991 (receivedfor review February 28, 1991) ABSTRACT The receptor for mouse hepatitis virus binds neither MHV-A59 virus nor anti-receptor mAb CC1, (MHV), a murine coronavirus, is a 110- to 120-kDa glycopro- we postulated that it has a mutation affecting the domain of tein on intestinal brush border membranes and hepatocyte the glycoprotein that normally would bind MHV and mAb membranes. The N-terminal 25-amino acid sequence of immu- CC1 (4). In this communication we demonstrate that the noaffinity-purified MHV receptor was identical to the pre- MHV receptor glycoprotein of BALB/c and Swiss Webster dicted mature N termini of two mouse genes related to human mice and its SJL/J homolog are members of the carcinoem- carcinoembryonic antigen (CEA) and was strongly homologous bryonic antigen (CEA) family of glycoproteins in the immu- to the N termini of members of the CEA family in humans and noglobulin superfamily. rats. Polyclonal antibodies to human CEA recognized the immunoaffinity-purified MHV receptor and the MHV receptor in liver membranes and intestinal brush border membranes MATERIALS AND METHODS from MHV-susceptible mouse strains. In membranes from Tissue Preparations and Tissue-Binding Assay. Intestinal MHV-resistant SJL/J mice, the anti-CEA antibodies recog- brush border membranes were prepared as described (3) from nized a homologous glycoprotein that failed to bind MHV. The adult female BALB/c and SJL/J mice. Mouse brain, colon, MHV receptor glycoprotein was detected in membranes of kidney, liver, lung, small intestine, spinal cord, and spleen BALB/c colon, small intestine, and liver, which are the were homogenized in phosphate-buffered saline (PBS; 0.137 principal targets for MHV replication in vivo. The MHV M NaCI/2.7 mM KCI/8.05 mM Na2HPO4.7H20/1.47 mM receptor glycoprotein resembled members of the human CEA KH2PO4) and centrifuged at 1000 x g for 5 min. The pellet family in molecular weight, acidic pl, extensive glycosylation, containing nuclei and debris was discarded, and particulate solubility in perchloric acid, and tissue distribution. Thus, the material was obtained by centrifuging the supernatant at MHV receptor is, to our knowledge, the first member of the 38,720 x g for 30 min. The pellet was washed by resuspending CEA family ofglycoproteins to be identified as a virus receptor. in PBS, centrifuging for 30 min at 38,720 x g, resuspended in PBS, and frozen at -70°C. Radiolabeled antibody binding to Coronaviruses are common pathogens that cause respiratory these preparations was quantitated as described (10). illness in humans and respiratory and/or enteric diseases in Protein Purification and Sequencing. MHV receptor from many animal species. The murine coronavirus, mouse hep- Swiss Webster mouse liver was immunoaffinity-purified on a atitis virus (MHV), infects mouse liver, epithelial cells of the mAb CC1 column as described (4) except that receptor was intestinal and respiratory tracts, macrophages, neural cells, eluted with a linear gradient of sodium thiocyanate from 1.0 and lymphocytes and is an excellent model for the study of to 5.0 M. MHV receptor protein from three 100-g batches viral infections in vivo (1, 2). Infection of cells is initiated were pooled. Concentrated receptor was electrophoresed on when the virus binds to a 110- to 120-kDa glycoprotein that an SDS/PAGE gel and blotted to poly (vinyl difluoride) is found on the plasma membranes of hepatocytes and membrane for N-terminal amino acid sequencing (11). Here, intestinal epithelial cells of MHV-susceptible BALB/c mice to maximize receptor on the membrane, 10 mM tetraborate (3). The MHV receptor has an acidic pI of 3.5-4.5 (4) and is (pH 9.6) was substituted for the standard 10 mM 3(Cyclo- highly glycosylated, with >35% of its total mass comprised of N-linked carbohydrate (R.K.W., unpublished data). hexylamino Propane Sulfonic acid (CAPS) (pH 11.0) buffer Monoclonal anti-receptor antibody CC1 (mAb CC1) blocks (G.S.J., unpublished data). Sequence was obtained from 10 binding of MHV to the receptor, prevents MHV infection of ,g of receptor glycoprotein at the Protein Sequencing Lab- cells in vitro (K.V.H., unpublished data), and inhibits virus oratory of the University of California at Davis. replication and dissemination in suckling mice in vivo (5). Antibodies and Antisera. The mAb CC1 directed against the The MHV receptor plays an important role in the patho- MHV receptor and the rabbit antibody directed against the genesis of MHV infections. Adult SJL/J mice are highly N-terminal 15 amino acids of the MHV receptor (anti-NTR) resistant to infection with MHV compared with other strains were produced as described (4). Rabbit antisera to human of mice such as BALB/c (6, 7). Resistance of SJL/J mice to CEA were from DAKO (Carpinteria, CA; A115, lot no. 067) MHV infection is a recessive trait mapped to the Hv-2 locus and Accurate Chemicals (Westbury, NY; AXL238, lot no. on mouse chromosome 7 (8, 9). Membranes from intestine 067G). Rabbit antiserum to human pregnancy-specific /3-1 and liver of SJL/J mice do not bind MHV or anti-receptor glycoprotein (PSG) was from Accurate Chemicals (West- mAb CC1, suggesting that resistance to infection is due to bury, NY; AXL 254, lot no. 24E). absence of a functional virus receptor (3, 4). SJL/J mice express a 100- to 110-kDa glycoprotein antigenically related Abbreviations: MHV, mouse hepatitis virus; CEA, carcinoembry- to the MHV receptor. Because this SJL/J receptor homolog onic antigen; mAb, monoclonal antibody; NTR, N-terminal 15 amino acids of MHV receptor; NCA, normal cross-reacting antigen; mmCGM2 and mmCGM4, mouse CEA-related CDNA clones; The publication costs of this article were defrayed in part by page charge mCGM4, rat CEA-related gene 4; BGP, human biliary glycoprotein payment. This article must therefore be hereby marked "advertisement" I; PSG2, human pregnancy-specific /3-1 glycoprotein (E). in accordance with 18 U.S.C. §1734 solely to indicate this fact. *To whom reprint requests should be addressed. 5533 Downloaded by guest on September 26, 2021 5534 Medical Sciences: Williams et al. Proc. Natl. Acad. Sci. USA 88 (1991) Biochemical Analysis. To test for solubility of receptor sequence homology to the MHV receptor. PSG2 is a member activity in perchloric acid, colon from adult female BALB/c of a subgroup of the CEA family that contains several mice was sliced longitudinally, cleaned in ice-cold Dulbec- glycoproteins that are highly expressed in human placenta co's PBS, and homogenized with a motorized homogenizer (19, 20). CEA, the prototype molecule of the CEA family, is (Tekmar Tissuemizer) for 2 min in sterile distilled water. An an acidic (pI 3-4) 180-kDa cell-surface glycoprotein with equal volume of 1.2 M perchloric acid was added to the -50o of its molecular mass being carbohydrate and is an homogenate, and after 15 min, precipitated proteins were important tumor marker of human adenocarcinoma of the centrifuged for 20 min at 35,000 x g at 4(C to form a pellet. colon, lung cancer, and breast cancer (14, 25). CEA is also Supernatant material was collected, neutralized to pH 7 with found, in much lower abundance, on normal colonic epithe- Tris base, desalted, and concentrated by using centrifugal lium. NCA-95 and NCA-55 share several antigenic sites with microconcentrators (Centricon 30, Amicon Div., W. R. CEA and are acidic glycoproteins expressed in normal colon, Grace, Danvers, MA). liver, lung, and spleen and on polymorphonuclear neutrophils Immunoblotting and Virus Blotting. SDS/polyacrylamide and macrophages. BGP is a 90-kDa CEA-related protein in gels (12) were transferred to nitrocellulose membranes and normal adult human liver (26). The predicted N-terminal probed with polyclonal antibodies or mAbs, followed by amino acid sequences ofthe rat genomic sequences rnCGM1, radioiodinated staphylococcal protein A and autoradiogra- rnCGM2, rnCGM3, rnCGM4, and mCGM5, which encode a phy (13). For virus-overlay protein blots (3), membrane family of genes related to human CEA (17), were also proteins were electrophoresed, blotted the same as for im- homologous to the N terminus of the MHV receptor. Of the munoblots, and then incubated with the A59 strain of MHV. rat CEA-like sequences, rnCGM4 was the most closely Bound virus was detected with anti-viral antibody followed related to the N terminus of the MHV receptor, with 64% by radioiodinated staphylococcal protein A as described (3). identity in the first 25 amino acids (Fig. 1). Rat ecto-ATPase, a 95- to 110-kDa molecular mass cell-surface nucleotidase found on the bile canalicular surface of hepatocytes and on RESULTS intestine brush borde,r is highly similar to human BGP (18, Affinity purification of the MHV receptor from Swiss Web- 27). The N terminus ofthe MHV receptor shares 60o identity ster mouse liver membranes (4) was scaled up to yield with rat ecto-ATPase. The predicted N-terminal amino acid sufficient glycoprotein to permit sequencing of the first 25 sequences from the two mouse CEA-like transcripts, amino acids. We searched the National Biomedical Research mmCGM2 and mmCGM4 (15), were identical to the N-ter- Foundation/Protein Identification Resource protein se- minal sequence we obtained from the MHV receptor protein.
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