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Cloning of Gp-340, a Putative Opsonin Receptor for Lung Surfactant Protein D

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Cloning of Gp-340, a Putative Opsonin Receptor for Lung Surfactant Protein D Proc. Natl. Acad. Sci. USA Vol. 96, pp. 10794–10799, September 1999 Immunology Cloning of gp-340, a putative opsonin receptor for lung surfactant protein D UFFE HOLMSKOV*†,JAN MOLLENHAUER‡,JENS MADSEN*, LARS VITVED*, JØRN GRØNLUND*, IDA TORNØE*, ANETTE KLIEM*, KENNETH B. M. REID§,ANNEMARIE POUSTKA‡, AND KARSTEN SKJØDT* *Department of Immunology and Microbiology, Institute of Medical Biology, University of Southern Denmark, Winsløwparken 19.1, DK-5000 Odense, Denmark; ‡Division of Molecular Genome Analysis, Deutsche Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany; and §Medical Research Council, Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, United Kingdom Edited by Mary Ellen Avery, Harvard Medical School, Boston, MA, and approved July 12, 1999 (received for review May 13, 1999) ABSTRACT Surfactant protein D (SP-D) is an oligomeric respect, SP-D is colocalized with IgA of the adaptive immune C type lectin that promotes phagocytosis by binding to mi- system (J.M. and U.H., unpublished work). Like the other crobial surface carbohydrates. A 340-kDa glycoprotein (gp- collectins, SP-D binds to repeating carbohydrate moieties on 340) has been shown to bind SP-D in the presence of calcium pathogenic microorganisms and is considered to be a pattern- but does so independently of carbohydrate recognition. This recognition molecule of the innate immune system (3). This protein exists both in a soluble form and in association with binding enhances phagocytosis and killing of microorganisms the membranes of alveolar macrophages. The primary struc- by neutrophils and alveolar macrophages (4, 5). The binding ture of gp-340 has been established by molecular cloning, also results in aggregation of the microorganisms and hin- which yielded a 7,686-bp cDNA sequence encoding a polypep- drance of infection. SP-D also binds directly to alveolar macrophages in the absence of microbial ligands, thereby tide chain of 2,413 amino acids. The domain organization mediating the generation of oxygen radicals (6), and acts as a features 13 scavenger receptor cysteine-rich (SRCR) domains, potent chemotactic agent for phagocytes (7, 8). SP-D has been each separated by an SRCR-interspersed domain, except for localized in endocytic vesicles and in lysosomal granules of SRCRs 4 and 5, which are contiguous. The 13 SRCR domains ͞ alveolar macrophages (9, 10), suggesting that it is involved in are followed by two C1r C1s Uegf Bmp1 domains separated by receptor-mediated uptake by these cells. SP-D has also been a 14th SRCR domain and a zona pellucida domain. gp-340 shown to inhibit T lymphocyte proliferation and IL-2 produc- seems to be an alternative spliced form of DMBT1. Reverse tion (11). transcription–PCR analysis showed that the main sites of SP-D interacts with surfactant-associated phospholipids in synthesis of gp-340 are lung, trachea, salivary gland, small vitro (12, 13), and mice made SP-D-deficient by gene targeting intestine, and stomach. Immunohistochemistry revealed showed a progressive accumulation of surfactant lipids in the strong staining for gp-340 in alveolar and other tissue mac- alveolar space. The SP-D null mice also showed an accumu- rophages. Immunostaining of the macrophage membrane was lation of alveolar macrophages, many of which were multinu- either uniform or focal in a way that suggested capping, cleated and foamy in appearance. The alveolar type II cells in whereas other macrophages showed strong intracellular these animals were hyperplastic and contained giant lamellar staining within the phagosome͞phagolysosome compart- bodies. These findings suggest that SP-D also plays a role in ments. In some macrophages, SP-D and gp-340 were located surfactant homeostasis (14, 15). in the same cellular compartment. Immunoreactive gp-340 No receptor responsible for the effector mechanisms of was also found in epithelial cells of the small intestine and in SP-D has yet been characterized. A molecule, designated the ducts of salivary glands. The distribution of gp-340 in gp-340, which copurifies with SP-D on carbohydrate affinity columns, has been isolated and shown to bind SP-D in a macrophages is compatible with a role as an opsonin receptor calcium-dependent manner (16). It has also been established for SP-D. that the binding of SP-D to gp-340 is a protein–protein interaction rather than a lectin–carbohydrate interaction. Re- Collectins are oligomeric proteins composed of C type lectin cently, it was shown that gp-340 also may bind to SP-A (17). domains connected to collagen regions (1). Three collectins Protein sequencing showed that gp-340 was a member of the are known in humans: mannan-binding lectin (MBL), a serum scavenger receptor cysteine-rich (SRCR) superfamily (16). protein, and the lung surfactant proteins A and D (SP-A and The gp-340 molecules exist both in a soluble form and in a SP-D), which are produced by epithelial cells mainly in the form associated with the alveolar macrophage membrane. In lung. The collectins play an important role in innate immunity the present paper, we describe the primary structure of gp-340 by binding to specific carbohydrate structures found on the and its tissue distribution. It seems probable that the molecular surfaces of pathogenic microorganisms, including bacteria, interaction between SP-D and gp-340 plays an important role viruses, yeasts, and parasitic protozoa. The binding promotes in innate immunity on mucosal surfaces. effector mechanisms such as aggregation, hindrance of infec- tion, activation of phagocytes, and initiation of phagocytosis. MATERIALS AND METHODS After binding to microbial surfaces, MBL activates the com- cDNA Cloning and Sequencing. A pool of 29-base oligonu- plement system through a complement activation pathway, the cleotide ‘‘guessmers’’ with a redundancy of 384 was synthesized MBL pathway, by using two recently identified serine pro- teases, MASP-1 and MASP-2, to activate C4 and C2 (2). SP-D is mainly produced by alveolar type II cells but is also This paper was submitted directly (Track II) to the Proceedings office. Abbreviations: EGF, epithelial growth factor; CUB, C1r͞C1s Uegf present in sweat, salivary, tear, and mammary glands and in Bmp1; SRCR, scavenger receptor cysteine-rich; RT-PCR, reverse epithelial cells throughout the gastrointestinal tract. In this transcription–PCR; kb, kilobase; ZP, zona pellucida; SID, SRCR- interspersed domain; Tm, transmembrane. The publication costs of this article were defrayed in part by page charge Data deposition: The sequences reported in this paper have been deposited in the European Molecular Biology Laboratory nucleotide payment. This article must therefore be hereby marked ‘‘advertisement’’ in sequence database (accession nos. AF159456 and AJ243212). accordance with 18 U.S.C. §1734 solely to indicate this fact. †To whom reprint requests should be addressed. E-mail: PNAS is available online at www.pnas.org. [email protected]. 10794 Downloaded by guest on September 24, 2021 Immunology: Holmskov et al. Proc. Natl. Acad. Sci. USA 96 (1999) 10795 in accordance with the codon usage of the underlined amino (dmbt1.1f, 5Ј-ATACCACCCTAGAGGACACACC-3Ј, and acids of the gp-340 peptide SWGTV(C)DDYWDTNDANV dmbt1.2r, 5Ј-GCAGTTCACCAAAATTCCTT-3Ј). The PCR (16). The ACG codon for threonine was omitted. The oligo- was performed as follows: an initial denaturation for 2 min at nucleotide sequence was 5Ј-TG(C͞T)GA(C͞T)GA(C͞ 94°C; 30 cycles of 20 s at 92°C, 30 s at 59°C, and 10 min at 68°C; T)TA(C͞T)TGGGA(C͞T)AC(A͞T͞C)AA(C͞T)GA(C͞ and a final extension for 10 min at 72°C. The PCR products T)GC-3Ј, which was end labeled with [␭-32P]ATP and T4 were cloned with the TOPO XL PCR Cloning Kit (Invitrogen) kinase and used for screening a ␭gt11 human lung cDNA according to the instructions of the supplier, and insert sizes library (CLONTECH). A single clone (gp-clone 1A) was were determined by NotI–HindIII digestion and subsequent obtained from 550,000 plaques. ␭DNA was prepared from this agarose gel electrophoresis. A DMBT1 clone with an insert of clone, and the insert was subcloned into pBluescript SK(ϩ) about 8 kilobases (kb; DMBT1͞8-kb.2) was selected for se- and sequenced. Sequencing was performed with the Cycle quencing by using the nested-deletion method (Nested Dele- Sequencing Kit (Amersham Pharmacia) on double-stranded tion Kit, Amersham Pharmacia). Sequencing was carried out templates with M13 and T7 primers on the vector as well as by using dye terminator chemistry (Amersham Pharmacia) and gp-340 internal oligonucleotides. Sequence analysis revealed automated DNA sequencers (Applied Biosystems model that gp-clone 1A was derived from a partially spliced mRNA. 373A͞377). The cDNA clone contained frameshift mutations One oligonucleotide was designed from the cDNA sequence of in codons 100 and 1,751 that were corrected by comparison gp-clone 1A R3OS, 5Ј-GATCCCTCCCTGCCCCTGCT-3Ј with the genomic sequence of the gene (18). (antisense), and used together with the ␭gt11 primer F11, 5Ј Immunohistochemistry. Normal human tissues and cell ACTCCTGGAGCCCGTCAGTAT-3Ј (sense), in a PCR with pellets from bronchoalveolar lavage fluid were fixed in 4% the gp-clone 1A used as template. The 600-bp PCR product (vol͞vol) formalin in PBS for 24 h and then conventionally was purified by electrophoresis through 0.8% (wt͞vol) agarose dehydrated and embedded in paraffin. A streptavidin-biotin and labeled with [␣-32P]dCTP by using R3OS and F11 as immunoperoxidase staining technique was used on the paraf- primers and a Klenow large fragment as DNA polymerase. fin-embedded sections, which were treated in a microwave This probe was used for screening an oligo(dT)-primed ␭gt11 oven to unmask epitopes (19). A monoclonal (Hyb 213-1) or human lung cDNA library (CLONTECH) and a random- and polyclonal antibody against gp-340 and a monoclonal (Hyb oligo(dT)-primed ␭gt11 human lung cDNA library (CLON- 245-1) antibody against SP-D were used, followed by biotin- TECH).
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