LSECtin
From CFGparadigms
LSECtin serves a model for other members of the C-type lectin family that are expressed on sinusoidal endothelial cells and facilitate viral infection, but lack endocytic function. The other main example of a protein with these characteristics is DC-SIGNR or L-SIGN, which is expressed in similar places and is also a target for various viruses, but has a different organization and ligand-binding characteristics.
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CFG Participating Investigators contributing to the understanding of this paradigm
Several PIs are working on expression of LSEctin, its ligand-binding specificity, its natural biological functions and its interactions with viral pathogens.
- PIs working on LSECtin include: Angel Corbi, Kurt Drickamer, Maureen Taylor
- PIs working on L-SIGN/DC-SIGNR include: Ben Appelmelk, Angel Corbi, Kurt Drickamer, Benhur Lee, Maureen Taylor, Yvette van Kooyk, Bill Weis
Progress toward understanding this GBP paradigm
This section documents what is currently known about LSECtin, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information about LSECtin can be found in its GBP Molecule Page in the CFG database.
Carbohydrate ligands
A major contribution from the CFG has been identification of the motif GlcNAcβ1-2Man as a common motif in all of the high affinity ligands. Competition studies have revealed that the affinity for this disaccharide is approximately 2 μM, making it one of the most specific and high affinity interactions known for any C-type lectin[1]. The glycoprotein CD44 on T cells has been identified as a potential glycoprotein ligand[2].
Cellular expression of GBP and ligands
Expression of LSECtin was originally described in sinusoidal endothelial cells of liver, lymph node and bone[3]. Subsequent studies have revealed expression in Kupffer cells in the liver as well[4]. Expression can also be induced in dendritic cell and macrophages under some conditions in vitro[5]. The glycoprotein CD44, a potential ligand, is expressed by T cells[2].
Biosynthesis of ligands
Glycans on viral envelope proteins that are ligands for LSECtin result from incomplete processing of glycans in the pathway for biosynthesis of complex N-linked glycans (Complex glycan biosynthesis), following addition of GlcNAc residues by GlcNAc transferases 1, 2, 4 and 5. (Mgat1) (Mgat2) (Mgat4) (Mgat5)
Structure
LSECtin is a type II transmembrane protein, with a C-terminal C-type carbohydrate-recognition domain (CRD) projected from the membrane surface by an intermediate neck domain. The short C-terminal domain is devoid of obvious signaling or internalization motifs. The receptor appears to be a disulfide-linked dimer[1].
Biological roles of GBP-ligand interaction
Unlike many cell surface glycan-binding receptors, LSECtin does not undergo constitutive recycling endocytosis, but binding of antibodies or ligands may lead to triggered internalization[1][3]. It has been suggested that in the liver LSECtin is an adhesion receptor that binds to CD44 on T cells and suppresses activation of T cells, thus contributing to general immune tolerance in the liver[6].
LSECtin is able to bind to envelope glycoproteins of Ebola virus and SARS coronavirus, which can be important either in infection or in presentation of virus to other cells[7][8].
CFG resources used in investigations
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for LSECtin.
Glycan profiling
Glycan profiling of mouse EL4 T lymphocytes shows that several of the most abundant glycans present bear terminal GlcNAcβ1-2Man structures which would be potential ligands for LSECtin.
N-linked glycans
All profiling data
Glycogene microarray
Probes for LSECtin have been included in version 4 of the CFG glycogene chip:
human probeset NM_198492
mouse probeset NM_029465.
Knockout mouse lines
LSECtin knockout mice were created by the CFG (LSECtin-total knockout and LSECtin-conditional knockout) and are in the queue for phenotype analysisin 2010/11.
Glycan array
Glycan array results for human LSECtin reveal a remarkable specificity for glycans containing one or more terminal GlcNAcβ1-2Man sequences (example). See all glycan array results for LSECtin here. See glycan array results for the related GBP DC-SIGNR here.
Related GBPs
L-SIGN / DC-SIGNR CFG data
References
- ↑ 1.0 1.1 1.2 Powlesland AS, Fisch T, Taylor ME, Smith DF, Tissot B, Dell A, Pöhlmann S, Drickamer K. (2008) A novel mechanism for LSECtin binding to Ebola virus surface glycoprotein through truncated glycans. J Biol Chem 283, 593-602
- ↑ 2.0 2.1 Tang L, Yang J, Tang X, Ying W, Qian X, He F (2010) The DC-SIGN family member LSECtin is a novel ligand of CD44 on activated T cells. Eur J Immunol 40, 1185-1191
- ↑ 3.0 3.1 Liu W, Tang L, Zhang G, Wei H, Cui Y, Guo L, Gou Z, Chen X, Jiang D, Zhu Y, Kang G, He F. (2004) Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J Biol Chem 279, 18748-18758
- ↑ Dominguez-Soto A, Aragoneses-Fenoll L, Martin-Gayo E, Martinez-Prats L, Colmenares M, Naranjo-Gomez M, Borras FE, Munoz P, Zubiaur M, Toribio ML, Delgado R, Corbi AL (2007) The DC-SIGN-related lectin LSECtin mediates antigen capture and pathogen binding by human myeloid cells. Blood 109, 5337-5345
- ↑ Domínguez-Soto A, Aragoneses-Fenoll L, Gómez-Aguado F, Corcuera MT, Clária J, García-Monzón C, Bustos M, Corbí AL (2009) The pathogen receptor liver and lymph node sinusoidal endothelial cell C-type lectin is expressed in human Kupffer cells and regulated by PU.1. Hepatology 49, 287-296
- ↑ Tang L, Yang J, Liu W, Tang X, Chen J, Zhao D, Wang M, Xu F, Lu Y, Liu B, Sun Q, Zhang L, He F (2009) Liver sinusoidal endothelial cell lectin, LSECtin, negatively regulates hepatic T-cell immune response. Gastroenterology 137, 1498-1508
- ↑ Gramberg T, Hofmann H, Möller P, Lalor PF, Marzi A, Geier M, Krumbiegel M, Winkler T, Kirchhoff F, Adams DH, Becker S, Münch J, Pöhlmann S. (2005) LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus. Virology 340, 224-236
- ↑ Gramberg T, Soilleux E, Fisch T, Lalor PF, Hofmann H, Wheeldon S, Cotterill A, Wegele A, Winkler T, Adams DH, Pöhlmann S. (2008) Interactions of LSECtin and DC-SIGN/DC-SIGNR with viral ligands: Differential pH dependence, internalization and virion binding. Virology 373, 189-201
Acknowledgements
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Maureen Taylor.
