DC-SIGN

Last updated
CD209
Protein CD209 PDB 1k9i.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CD209 , CDSIGN, CLEC4L, DC-SIGN, DC-SIGN1, CD209 molecule, hDC-SIGN
External IDs OMIM: 604672 MGI: 2157948 HomoloGene: 128353 GeneCards: CD209
Orthologs
SpeciesHumanMouse
Entrez

30835

170780

Ensembl

ENSG00000090659

ENSMUSG00000040197

UniProt

Q9NNX6

Q91ZW7

RefSeq (mRNA)

NM_130905

RefSeq (protein)

NP_570975

Location (UCSC) Chr 19: 7.74 – 7.75 Mb Chr 8: 3.9 – 3.9 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) also known as CD209 (Cluster of Differentiation 209) is a protein which in humans is encoded by the CD209 gene. [5]

Contents

DC-SIGN is a C-type lectin receptor present on the surface of both macrophages and dendritic cells. DC-SIGN on macrophages recognises and binds with high affinity to high-mannose type N-glycans, a class of PAMPs (pathogen associated molecular patterns) commonly found on viruses, bacteria and fungi. This binding interaction activates phagocytosis. [6] On myeloid and pre-plasmacytoid dendritic cells DC-SIGN mediates dendritic cell rolling interactions with blood endothelium and activation of CD4+ T cells, as well as recognition of pathogen haptens.

Function

DC-SIGN is a C-type lectin and has a high affinity for the ICAM3 molecule. [7] 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. [8] [9] [10] Binding to DC-SIGN can promote HIV and Hepatitis C virus to infect target cells (T-cells and hepatocytes, respectively). [9] [10]

Besides functioning as an adhesion molecule, recent studies have also shown that DC-SIGN can initiate innate immunity by modulating toll-like receptors, [11] 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. [12]

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. [13]

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. [14]

SARS-CoV-2

DC-sign and its counterpart L-SIGN (CD 209L) 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. [15] [16] 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. [17] 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. [18] This process seems to be exclusive for DC/L-sign interaction. This complexity in the recognition patterns and functions of these receptors is similar to what has been observed in other viruses like HIV and ebola virus.

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 [19] ) 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. [20]

Related Research Articles

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Lectin</span> Carbohydrate-binding protein

Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in recognition at the cellular and molecular level and play numerous roles in biological recognition phenomena involving cells, carbohydrates, and proteins. Lectins also mediate attachment and binding of bacteria, viruses, and fungi to their intended targets.

<i>Adenoviridae</i> Family of viruses

Adenoviruses are medium-sized, nonenveloped viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from their initial isolation from human adenoids in 1953.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">Envelope glycoprotein GP120</span> Glycoprotein exposed on the surface of the HIV virus

Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1984. The 120 in its name comes from its molecular weight of 120 kDa. Gp120 is essential for virus entry into cells as it plays a vital role in attachment to specific cell surface receptors. These receptors are DC-SIGN, Heparan Sulfate Proteoglycan and a specific interaction with the CD4 receptor, particularly on helper T-cells. Binding to CD4 induces the start of a cascade of conformational changes in gp120 and gp41 that lead to the fusion of the viral membrane with the host cell membrane. Binding to CD4 is mainly electrostatic although there are van der Waals interactions and hydrogen bonds.

<span class="mw-page-title-main">Toll-like receptor 2</span> One of the toll-like receptors and plays a role in the immune system

Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the TLR2 gene. TLR2 has also been designated as CD282. TLR2 is one of the toll-like receptors and plays a role in the immune system. TLR2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system.

<span class="mw-page-title-main">Mannan-binding lectin</span> Mammalian protein found in Homo sapiens

Mannose-binding lectin (MBL), also called mannan-binding lectin or mannan-binding protein (MBP), is a lectin that is instrumental in innate immunity as an opsonin and via the lectin pathway.

<span class="mw-page-title-main">Langerin</span>

Langerin (CD207) is a type II transmembrane protein which is encoded by the CD207 gene in humans. It was discovered by scientists Sem Saeland and Jenny Valladeau as a main part of Birbeck granules. Langerin is C-type lectin receptor on Langerhans cells (LCs) and in mice also on dermal interstitial CD103+ dendritic cells (DC) and on resident CD8+ DC in lymph nodes.

Visna-maedi virus from the genus Lentivirus and subfamily Orthoretrovirinae, is a retrovirus that causes encephalitis and chronic pneumonitis in sheep. It is known as visna when found in the brain, and maedi when infecting the lungs. Lifelong, persistent infections in sheep occur in the lungs, lymph nodes, spleen, joints, central nervous system, and mammary glands; The condition is sometimes known as ovine progressive pneumonia (OPP), particularly in the United States, or Montana sheep disease. White blood cells of the monocyte/macrophage lineage are the main target of the virus.

<span class="mw-page-title-main">ICAM3</span> Mammalian protein found in Homo sapiens

Intercellular adhesion molecule 3 (ICAM3) also known as CD50, is a protein that in humans is encoded by the ICAM3 gene. The protein is constitutively expressed on the surface of leukocytes, which are also called white blood cells and are part of the immune system. ICAM3 mediates adhesion between cells by binding to specific integrin receptors. It plays an important role in the immune cell response through its facilitation of interactions between T cells and dendritic cells, which allows for T cell activation. ICAM3 also mediates the clearance of cells undergoing apoptosis by attracting and binding macrophages, a type of cell that breaks down infected or dying cells through a process known as phagocytosis, to apoptotic cells.

<span class="mw-page-title-main">CD69</span> Human lectin protein

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

<span class="mw-page-title-main">CLEC4M</span> Protein-coding gene in the species Homo sapiens

C-type lectin domain family 4 member M is a protein that in humans is encoded by the CLEC4M gene. CLEC4M has also been designated as CD299.

<span class="mw-page-title-main">SLAMF1</span> Protein-coding gene in humans

Signaling lymphocytic activation molecule 1 is a protein that in humans is encoded by the SLAMF1 gene. Recently SLAMF1 has also been designated CD150.

<span class="mw-page-title-main">CLEC7A</span> Protein-coding gene in humans

C-type lectin domain family 7 member A or Dectin-1 is a protein that in humans is encoded by the CLEC7A gene. CLEC7A is a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. The encoded glycoprotein is a small type II membrane receptor with an extracellular C-type lectin-like domain fold and a cytoplasmic domain with a partial immunoreceptor tyrosine-based activation motif. It functions as a pattern-recognition receptor for a variety of β-1,3-linked and β-1,6-linked glucans from fungi and plants, and in this way plays a role in innate immune response. Expression is found on myeloid dendritic cells, monocytes, macrophages and B cells. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. This gene is closely linked to other CTL/CTLD superfamily members on chromosome 12p13 in the natural killer gene complex region.

<span class="mw-page-title-main">CD226</span> Protein-coding gene in the species Homo sapiens

CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.

<span class="mw-page-title-main">KLRG1</span> Protein-coding gene in humans

Killer cell lectin-like receptor subfamily G member 1 is a protein that in humans is encoded by the KLRG1 gene.

<span class="mw-page-title-main">CLEC1B</span> Protein-coding gene in humans

C-type lectin domain family 1 member B is a protein that in humans is encoded by the CLEC1B gene.

Feline coronavirus (FCoV) is a positive-stranded RNA virus that infects cats worldwide. It is a coronavirus of the species Alphacoronavirus 1, which includes canine coronavirus (CCoV) and porcine transmissible gastroenteritis coronavirus (TGEV). FCoV has two different forms: feline enteric coronavirus (FECV), which infects the intestines, and feline infectious peritonitis virus (FIPV), which causes the disease feline infectious peritonitis (FIP).

<span class="mw-page-title-main">Paired receptors</span>

Paired receptors are pairs or clusters of receptor proteins that bind to extracellular ligands but have opposing activating and inhibitory signaling effects. Traditionally, paired receptors are defined as homologous pairs with similar extracellular domains and different cytoplasmic regions, whose genes are located together in the genome as part of the same gene cluster and which evolved through gene duplication. Homologous paired receptors often, but not always, have a shared ligand in common. More broadly, pairs of receptors have been identified that exhibit paired functional behavior - responding to a shared ligand with opposing intracellular signals - but are not closely homologous or co-located in the genome. Paired receptors are highly expressed in the cells of the immune system, especially natural killer (NK) and myeloid cells, and are involved in immune regulation.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000090659 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040197 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Curtis BM, Scharnowske S, Watson AJ (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. 89 (17): 8356–8360. Bibcode:1992PNAS...89.8356C. doi: 10.1073/pnas.89.17.8356 . PMC   49917 . PMID   1518869.
  6. ↑ McGreal EP, Miller JL, Gordon S (February 2005). "Ligand recognition by antigen-presenting cell C-type lectin receptors". Current Opinion in Immunology. 17 (1): 18–24. doi:10.1016/j.coi.2004.12.001. PMC   7126011 . PMID   15653305.
  7. ↑ Khoo US, Chan KY, Chan VS, Lin CL (August 2008). "DC-SIGN and L-SIGN: the SIGNs for infection". Journal of Molecular Medicine. 86 (8): 861–874. doi:10.1007/s00109-008-0350-2. PMC   7079906 . PMID   18458800.
  8. ↑ Lozach PY, Burleigh L, Staropoli I, Amara A (2007). "The C Type Lectins DC-SIGN and L-SIGN". Glycovirology Protocols. Methods in Molecular Biology. Vol. 379. pp. 51–68. doi:10.1007/978-1-59745-393-6_4. ISBN   978-1-58829-590-3. PMC   7122727 . PMID   17502670.
  9. 1 2 Lozach PY, Amara A, Bartosch B, Virelizier JL, Arenzana-Seisdedos F, Cosset FL, Altmeyer R (July 2004). "C-type lectins L-SIGN and DC-SIGN capture and transmit infectious hepatitis C virus pseudotype particles". The Journal of Biological Chemistry. 279 (31): 32035–32045. doi: 10.1074/jbc.M402296200 . PMID   15166245.
  10. 1 2 Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, et al. (March 2000). "DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells". Cell. 100 (5): 587–597. doi: 10.1016/S0092-8674(00)80694-7 . PMID   10721995. S2CID   15041781.
  11. ↑ den Dunnen J, Gringhuis SI, Geijtenbeek TB (July 2009). "Innate signaling by the C-type lectin DC-SIGN dictates immune responses". Cancer Immunology, Immunotherapy. 58 (7): 1149–1157. doi: 10.1007/s00262-008-0615-1 . PMID   18998127.
  12. ↑ Aarnoudse CA, Garcia Vallejo JJ, Saeland E, van Kooyk Y (February 2006). "Recognition of tumor glycans by antigen-presenting cells". Current Opinion in Immunology. 18 (1): 105–111. doi:10.1016/j.coi.2005.11.001. PMID   16303292.
  13. ↑ van den Berg LM, Geijtenbeek TB (2012). "Antiviral Immune Responses by Human Langerhans Cells and Dendritic Cells in HIV-1 Infection". HIV Interactions with Dendritic Cells. Advances in Experimental Medicine and Biology. Vol. 762. pp. 45–70. doi:10.1007/978-1-4614-4433-6_2. ISBN   978-1-4614-4432-9. PMID   22975871.
  14. ↑ Muñoz A, Sigwalt D, Illescas BM, Luczkowiak J, Rodríguez-Pérez L, Nierengarten I, et al. (January 2016). "Synthesis of giant globular multivalent glycofullerenes as potent inhibitors in a model of Ebola virus infection". Nature Chemistry. 8 (1): 50–57. Bibcode:2016NatCh...8...50M. doi:10.1038/nchem.2387. hdl: 10261/127820 . PMID   27055288.
  15. ↑ Rahimi N (December 2020). "C-type Lectin CD209L/L-SIGN and CD209/DC-SIGN: Cell Adhesion Molecules Turned to Pathogen Recognition Receptors". Biology. 10 (1): 1. doi: 10.3390/biology10010001 . PMC   7822156 . PMID   33375175.
  16. ↑ Gao C, Zeng J, Jia N, Stavenhagen K, Matsumoto Y, Zhang H, Li J, Hume AJ, Mühlberger E (2020-07-30). SARS-CoV-2 Spike Protein Interacts with Multiple Innate Immune Receptors (Report). Biochemistry. doi:10.1101/2020.07.29.227462. PMC   7402034 . PMID   32766577.
  17. ↑ Amraei R, Yin W, Napoleon MA, Suder EL, Berrigan J, Zhao Q, et al. (July 2021). "CD209L/L-SIGN and CD209/DC-SIGN Act as Receptors for SARS-CoV-2". ACS Central Science. 7 (7): 1156–1165. doi:10.1021/acscentsci.0c01537. PMC   8265543 . PMID   34341769.
  18. ↑ Thépaut M, Luczkowiak J, Vivès C, Labiod N, Bally I, Lasala F, et al. (May 2021). Pekosz A (ed.). "DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist". PLOS Pathogens. 17 (5): e1009576. doi: 10.1371/journal.ppat.1009576 . PMC   8136665 . PMID   34015061.
  19. ↑ Davis CW, Nguyen HY, Hanna SL, Sánchez MD, Doms RW, Pierson TC (2006). "West Nile Virus Discriminates between DC-SIGN and DC-SIGNR for Cellular Attachment and Infection". Journal of Virology. 80 (3): 1290–1301. doi: 10.1128/JVI.80.3.1290-1301.2006 . PMC   1346927 . PMID   16415006.
  20. ↑ Ortiz M, Kaessmann H, Zhang K, Bashirova A, Carrington M, Quintana-Murci L, Telenti A (September 2008). "The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates". Genes and Immunity. 9 (6): 483–492. doi:10.1038/gene.2008.40. PMC   2701223 . PMID   18528403.

Further reading

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