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Originally published In Press as doi:10.1074/jbc.M009807200 on May 3, 2001

J. Biol. Chem., Vol. 276, Issue 35, 33196-33212, August 31, 2001
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Extensive Repertoire of Membrane-bound and Soluble Dendritic Cell-specific ICAM-3-grabbing Nonintegrin 1 (DC-SIGN1) and DC-SIGN2 Isoforms
INTER-INDIVIDUAL VARIATION IN EXPRESSION OF DC-SIGN TRANSCRIPTS*,

Srinivas MummidiDagger §, Gabriel Catano§, LeeAnn Lam§, Angelina Hoefle§, Vanessa Telles§, Kazi Begum§, Fabio Jimenez§, Seema S. AhujaDagger ||, and Sunil K. AhujaDagger §**

From the Dagger  South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, Texas 78229-4404 and the Divisions of § Infectious Diseases and || Nephrology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900

Expression in dendritic cells (DCs) of DC-SIGN, a type II membrane protein with a C-type lectin ectodomain, is thought to play an important role in establishing the initial contact between DCs and resting T cells. DC-SIGN is also a unique type of human immunodeficiency virus-1 (HIV-1) attachment factor and promotes efficient infection in trans of cells that express CD4 and chemokine receptors. We have identified another gene, designated here as DC-SIGN2, that exhibits high sequence homology with DC-SIGN. Here we demonstrate that alternative splicing of DC-SIGN1 (original version) and DC-SIGN2 pre-mRNA generates a large repertoire of DC-SIGN-like transcripts that are predicted to encode membrane-associated and soluble isoforms. The range of DC-SIGN1 mRNA expression was significantly broader than previously reported and included THP-1 monocytic cells, placenta, and peripheral blood mononuclear cells (PBMCs), and there was cell maturation/activation-induced differences in mRNA expression levels. Immunostaining of term placenta with a DC-SIGN1-specific antiserum showed that DC-SIGN1 is expressed on endothelial cells and CC chemokine receptor 5 (CCR5)-positive macrophage-like cells in the villi. DC-SIGN2 mRNA expression was high in the placenta and not detectable in PBMCs. In DCs, the expression of DC-SIGN2 transcripts was significantly lower than that of DC-SIGN1. Notably, there was significant inter-individual heterogeneity in the repertoire of DC-SIGN1 and DC-SIGN2 transcripts expressed. The genes for DC-SIGN1, DC-SIGN2, and CD23, another Type II lectin, colocalize to an ~85 kilobase pair region on chromosome 19p13.3, forming a cluster of related genes that undergo highly complex alternative splicing events. The molecular diversity of DC-SIGN-1 and -2 is reminiscent of that observed for certain other adhesive cell surface proteins involved in cell-cell connectivity. The generation of this large collection of polymorphic cell surface and soluble variants that exhibit inter-individual variation in expression levels has important implications for the pathogenesis of HIV-1 infection, as well as for the molecular code required to establish complex interactions between antigen-presenting cells and T cells, i.e. the immunological synapse.

* This work was supported in part by National Institutes of Health Grants AI43279 and AI46326 (to S. K. A.).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.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Figs. 1-3.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AY042221 through AY042240.

These authors contributed equally to this work.

** Recipient of an Elizabeth Glaser Scientist award from the Elizabeth Glaser Pediatric AIDS Foundation and a Burroughs Wellcome Clinical Scientist Award in Translational Research. To whom correspondence should be addressed: Division of Infectious Diseases, Dept. of Medicine (Mail Code 7880), University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900. Tel.: 210-567-6511; Fax: 210-567-4654; E-mail: ahujas@uthscsa.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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