DC-SIGN

Function

DC-SIGN is a C-type lectin and has a high affinity for the ICAM3 molecule. It binds various microorganisms by recognizing high-mannose-containing glycoproteins on their surface, and can function as a co-receptor for several viruses such as HIV and Hepatitis C. Binding to DC-SIGN can promote HIV and Hepatitis C virus to infect target cells (T-cells and hepatocytes, respectively).

Besides functioning as an adhesion molecule, recent studies have also shown that DC-SIGN can initiate innate immunity by modulating toll-like receptors, though the detailed mechanism is not yet known. DC-SIGN together with other C-type lectins is involved in recognition of tumors by dendritic cells. DC-SIGN is also a potential engineering target for dendritic cell based cancer vaccine.

Clinical significance

HIV infection

This molecule is involved in the initial stages of the human immunodeficiency virus infection, as the HIV gp120 molecule causes co-internalization of the DC-SIGN molecule and HIV virus particle (virion). The dendritic cell then migrates to the cognate lymphoid organ, whereupon recycling of the DC-SIGN/HIV virion complex to the cell periphery facilitates HIV infection of CD4+ T cells by interaction between DC-SIGN and ICAM-3.

Ebola infection

Different studies have demonstrated that the ebola virus infection process starts when the virus reaches the cellular DC-SIGN receptor to infect the dendritic cells (of the immune system). In 2015 European researchers designed a "giant" molecule formed by thirteen fullerenes covered by carbohydrates which, by blocking DC-SIGN receptor, are able to inhibit the cell infection by an artificial ebola virus model. These antiviral molecules decorated with specific carbohydrates (sugars) present affinity by the receptor used as an entry point to infect the cell and act blocking it, thus inhibiting the infection in a sub-nanomolar range.

SARS-CoV-2

Similarly to HIV-1 gp120 binding, both DC-SIGN and its homologue L-SIGN (CD209L or CD299) have also been identified as receptors facilitating the entry of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human cells. Significant CD209L expression has been revealed in lung and kidney epithelia and endothelia and interactions with SARS-CoV-2 Spike protein (S protein) have been demonstrated in vitro. CD209L also exhibits interaction with Angiotensin-converting enzyme-2 (ACE2), suggesting a potential role for CD209L-ACE2 heterodimerization in SARS-CoV-2 entry and infection in cell types expressing both proteins. It is shown that DC/L-SIGN can enhance viral infection and dissemination by contributing to additional routes of infection mediated by the S protein in a process called trans-infection. This process seems to be exclusive for DC/L-SIGN interaction. This complexity in the recognition patterns and functions of these C-lectin receptors is similar to what has been described for other viruses (like HIV and Ebola virus) and thus both DC/L-SIGN are considered as pattern recognition receptors (PRR).

Gene family

DC-SIGN/CD209 is an animal "C-lectin", a large and diverse family of proteins found in both prokaryotes and eukaryotes most of which are functional lectins, meaning they bind carbohydrate ligands, and whose ligand-binding affinity requires calcium (hence "C-lectin"). Among the animal C-lectins, a subfamily known as the ASGR (asialoglycoprotein receptors) group contains several sub-sub-families, many of which are important to innate immunity.

A cluster of genes in both humans and mice contains three related members of the "DC Receptor" class, so named because of their homology to DC-SIGN. Of these, CD23 is, however, not expressed on dendritic cells but is a characteristic surface molecule of B lymphocytes, and LSectin (CLEC4G) is expressed on the sinusoidal endothelium of the liver. The third gene group consists of multiple paralogues of CD209. Thus, both primates and mice have multiple paralogues of CD209 more closely related to each other within the species than to their orthologous counterparts in the other species. Higher primates have at least three DC-SIGN genes, DC-SIGN, DC-SIGNL1 (also known as DC-SIGNR or L-SIGN) and DC-SIGNL2, although not all three are present in every species; DC-SIGNL2 has not been detected in humans. Eight paralogous of DC-SIGN have been reported in the laboratory mouse strain C57BL/6; these go by the names DC-SIGN, DC-SIGNR2...DC-SIGNR8. DC-SIGNR6 is a pseudogene. The genes labeled "DC-SIGN" in the human and mouse are thus not unique orthologues, although they resemble each other functionally and by being expressed on dendritic cells. Other members of the mouse CD209 gene group are differentially expressed on different cell types. For example, DC-SIGNR1 is expressed largely on macrophages in the marginal zones of the spleen and in the medulla of lymph nodes.

References

References

1. (September 1992). "Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120". Proceedings of the National Academy of Sciences of the United States of America.
2. (February 2005). "Ligand recognition by antigen-presenting cell C-type lectin receptors". Current Opinion in Immunology.
3. (August 2008). "DC-SIGN and L-SIGN: the SIGNs for infection". Journal of Molecular Medicine.
4. (2007). "Glycovirology Protocols".
5. (July 2004). "C-type lectins L-SIGN and DC-SIGN capture and transmit infectious hepatitis C virus pseudotype particles". The Journal of Biological Chemistry.
6. (March 2000). "DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells". Cell.
7. (July 2009). "Innate signaling by the C-type lectin DC-SIGN dictates immune responses". Cancer Immunology, Immunotherapy.
8. (February 2006). "Recognition of tumor glycans by antigen-presenting cells". Current Opinion in Immunology.
9. (2012). "HIV Interactions with Dendritic Cells".
10. (January 2016). "Synthesis of giant globular multivalent glycofullerenes as potent inhibitors in a model of Ebola virus infection". Nature Chemistry.
11. (October 2021). "Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies". Nature.
12. (December 2020). "C-type Lectin CD209L/L-SIGN and CD209/DC-SIGN: Cell Adhesion Molecules Turned to Pathogen Recognition Receptors". Biology.
13. (July 2020). "SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors".
14. (July 2021). "CD209L/L-SIGN and CD209/DC-SIGN Act as Receptors for SARS-CoV-2". ACS Central Science.
15. (May 2021). "DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist". PLOS Pathogens.
16. (2006). "West Nile Virus Discriminates between DC-SIGN and DC-SIGNR for Cellular Attachment and Infection". Journal of Virology.
17. (September 2008). "The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates". Genes and Immunity.