SIGLEC

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Sialic acid binding Ig-like lectin family
Identifiers
SymbolSIGLEC
Membranome 210

Siglecs(Sialic acid-binding immunoglobulin-type lectins) are cell surface proteins that bind sialic acid. They are found primarily on the surface of immune cells and are a subset of the I-type lectins. There are 14 different mammalian Siglecs, providing an array of different functions based on cell surface receptor-ligand interactions. [1]

Contents

History

The first described candidate Siglec was Sialoadhesin (Siglec-1/CD169) a lectin-like adhesion protein on macrophages. [2] Parallel studies by Ajit Varki and colleagues on the previously cloned CD22 (a B cell surface protein involved in adhesion and activation) showed direct evidence for sialic acid recognition. The subsequent cloning of Sialoadhesin by Crocker revealed homology to CD22 (Siglec-2), CD33 (Siglec-3) and myelin-associated glycoprotein (MAG/Siglec-4), leading to the proposal for a family of "Sialoadhesins". Varki then suggested the term Siglec as a better alternative and as a subset of I-type (Ig-type) lectins. This nomenclature was agreed upon and has been adopted by almost all investigators working on these molecules (by convention, Siglecs are always capitalised.) Several additional Siglecs (Siglecs 5–12) have been identified in humans that are highly similar in structure to CD33 and so are collectively referred to as "CD33-related Siglecs". [3] Further Siglecs have been identified including Siglec-14 and Siglec-15. Siglecs have been characterized into two distinct groups: the first and highly conserved-across-mammals group composed of Sialoadhesins, CD22, MAG, and Siglec-15, and a second group comprising Siglecs closely related to CD33. [4] Others such as Siglec-8 and Siglec-9 have homologues in mice and rats (Siglec-F and Siglec-E respectively in both). Humans have a higher number of Siglecs than mice and so the numbering system was based on the human proteins. [5]

Structure

Sialoadhesin's variable immunoglobulin domain in complex with a sialylated glycan. Glycan carbons are in purple, protein carbons in green, oxygens in red, nitrogens in blue and hydrogens in white. Sialoadhesin salt bridge with sialylated glycan.png
Sialoadhesin's variable immunoglobulin domain in complex with a sialylated glycan. Glycan carbons are in purple, protein carbons in green, oxygens in red, nitrogens in blue and hydrogens in white.

Siglecs are Type I transmembrane proteins where the NH3+-terminus is in the extracellular space and the COO−-terminus is cytosolic. [6] Each Siglec contains an N-terminal V-type immunoglobulin domain (Ig domain) which acts as the binding receptor for sialic acid. These lectins are placed into the group of I-type lectins because the lectin domain is an immunoglobulin fold. All Siglecs are extended from the cell surface by C2-type Ig domains which have no binding activity. Siglecs differ in the number of these C2-type domains. [5] As these proteins contain Ig domains, they are members of the Immunoglobulin superfamily (IgSF).

Most Siglecs, such as CD22 and the CD33-related family, contain ITIMs (Immunoreceptor tyrosine-based inhibitory motifs) in their cytosolic region. [6] These act to down-regulate signalling pathways involving phosphorylation, such as those induced by ITAMs (Immunoreceptor tyrosine-based activation motifs). [7] Some, however, like Siglec-14, contain positive amino acid residues that help dock ITAM-containing adaptor proteins such as DAP12. [1]

Ligand binding

Due to the acidic nature of sialic acid, Siglec active sites contain a conserved arginine residue which is positively charged at physiological pH. This amino acid forms salt bridges with the carboxyl group of the sugar residue. [5] This is best seen in Sialoadhesin, where arginine at position 97 forms salt bridges with the COO− group of the sialic acid, producing a stable interaction. [8] Each lectin domain is specific for the linkage that connects sialic acid to the glycan. Sialic acid contains numerous hydroxyl groups which can be involved in the formation of glycosidic linkages. Most sialic acids are bonded via the 2, 3, 6 and occasionally 8 hydroxyl groups (number dependent on the carbon to which they are attached), in an α anomeric configuration. The specificity of each Siglec is due to different chemical interactions between the sugar ligand and the Siglec amino acids. The position in space of the individual groups on the sugar and the protein amino acids affects the sialic acid linkage to which each Siglec binds. For example, Sialoadhesin preferentially binds α2,3 linkages over α2,6 linkages. [8]

Function

Simplified schematic representation of the CD22 and B-cell receptor signalling process. pTyr refers to phosphotyrosine. The blocked line represents inhibition. Schematic representation of the CD22 and B-cell receptor signalling process.png
Simplified schematic representation of the CD22 and B-cell receptor signalling process. pTyr refers to phosphotyrosine. The blocked line represents inhibition.

The primary function of Siglecs is to bind glycans containing sialic acids. These receptor-glycan interactions can be used in cell adhesion, cell signalling and others. The function of Siglecs is limited to their cellular distribution. For example, MAG is found only on oligodendrocytes and schwann cells whereas Sialoadhesin is localised to macrophages.

Most Siglecs are short and do not extend far from the cell surface. This prevents most Siglecs from binding to other cells as mammalian cells are covered in sialic acid-containing glycans. This means that the majority of Siglecs only bind ligands on the surface of the same cell, so called cis -ligands, as they are "swamped" by glycans on the same cell. One exception is Sialoadhesin which contains 16 C2-Ig domains, producing a long, extended protein allowing it to bind trans-ligands, i.e. ligands found on other cells. Others, such as MAG, have also been shown to bind trans-ligands.

Signalling

Due to their ITIM-containing cytoplasmic regions, most Siglecs interfere with cellular signalling, inhibiting immune cell activation. Once bound to their ligands, Siglecs recruit inhibitory proteins such as SHP phosphatases via their ITIM domains. [9] The tyrosine contained within the ITIM is phosphorylated after ligand binding and acts as a docking site for SH2 domain-containing proteins like SHP phosphatases. This leads to de-phosphorylation of cellular proteins, down-regulating activating signalling pathways.

Examples of negative signalling:

Siglec-14 contains an arginine residue in its transmembrane region. [12] This binds to the ITAM-containing DAP10 and DAP12 proteins. When bound to its ligand, Siglec-14 leads to activation of cellular signalling pathways via the DAP10 and DAP12 proteins. [6] These proteins up-regulate phosphorylation cascades involving numerous cellular proteins, leading to cellular activation. Siglec-14 appears to co-localise with Siglec-5, and as this protein inhibits cellular signalling pathways, co-ordinate opposing functions within immune cells. [12]

Phagocytosis and adhesion

Siglecs that can bind trans-ligands, such as Sialoadhesin, allow cell-cell interactions to take place. These glycan-Siglec interactions allow cells to bind one another, allowing signalling in some cases, or in the case of Sialoadhesin, pathogen uptake. Sialoadhesin's function was originally thought to be important in binding to red blood cells. Sialoadhesin lacks a cytosolic ITIM or a positive residue to bind ITAM-containing adaptors and so is thought not to influence signalling. Studies show that this protein is involved in phagocytosis of bacteria that contain highly sialylated glycan structures such as the lipopolysaccharide of Neisseria meningitidis . [13] Binding to these structures allows the macrophage to phagocytose these bacteria, clearing the system of pathogens.

Siglec-7 is also used in binding to pathogens such as Campylobacter jejuni . This occurs in a sialic acid-dependent manner and brings NK cells and monocytes, on which Siglec-7 is expressed, into contact with these bacteria. [14] The NK cell is then able to kill these foreign pathogens.

Knock-out studies

Knock-out studies are often used to uncover the function proteins have within a cell. Mice are often used as they express orthologous proteins of ours, or extremely similar homologues.

Some examples of knock-out Siglecs include:

Human/Primate Siglecs

NameCellular distribution [6] Sialic acid linkage specificity [5] No. of C2-Ig domains [6] ITIM or positive residue [6]
Siglec-1 (Sialoadhesin)Macrophagesα2,3>α2,616None
Siglec-2 (CD22)B cellsα2,66ITIM
Siglec-3 (CD33)Myeloid progenitors, Monocytesα2,6>α2,3 [17] 1ITIM
Siglec-4 (MAG)Myelinα2,3>α2,64None
Siglec-5 Neutrophils, Monocytesα2,33ITIM
Siglec-6Trophoblastsα2,62ITIM
Siglec-7 NK cellsα2,8>α2,6>α2,32ITIM
Siglec-8 Eosinophilsα2,3>α2,62ITIM
Siglec-9 Monocytes, Neutrophils, Dendritic cellsα2,3=α2,6 (prefers sulfated residues)2ITIM
Siglec-10 B cellsα2,3=α2,64ITIM
Siglec-11B cellsα2,84ITIM
Siglec-12 [18] MacrophagesNo binding [5] 2ITIM
Siglec-13 [19] Chimpanzee monocytes
Siglec-14Unknownα2,6 [12] 2Arginine [12]
Siglec-15Osteoclasts, Macrophages, DCs [20] [21] α2,6 [22] 1Lysine [22]
Siglec-16 [23] Tissue macrophages
Siglec-17 [19] NK cells

This table briefly summarises the cellular distribution of each human/primate Siglec; the linkage specificity each has for sialic acid binding; the number of C2-Ig domains it contains; and whether it contains an ITIM or a positive residue to bind ITAM-containing adaptor proteins. References in the column headings correspond to all information displayed in that column, unless other references are shown. Siglec-12 information is referenced by [18] only, excluding the linkage specificity.

Mimetics

Many pathologies have been linked to the spontaneous interactions between sialic acid and the immunosuppressive sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on immune cells such as cancer, [24] HIV-1 [25] and Group B Strep Infection. [26] [27] The sialic acid family branches from glycans, sugar chains comprising various monosaccharides that cover the membrane of every living cell and display a staggering structural diversity. Sialic acids function in protein folding, neural development, cellular interactions, among many other physiological processes. As sialic acids are abundantly expressed in vertebrates and not in microorganisms, they are considered self-antigens or self-structures that play major role in inhibiting harmful immune system activity by regulating neutrophils and B cell tolerance. [28]

Within the immune system, Siglecs, especially those related to CD33, sialic acid and Siglec-binding pathogens are subjected to the runaway Red Queen co-evolution phenomenon by a selection pressure that maintains innate immune system's capacity for self-recognition and ensures prevention of autoimmunity diseases. [29] [30] This evolutionary chain and incessant mutations have made Siglecs one of the most rapidly evolving gene, evidenced by both intra- and inter-species differences. [30] The polymorphism of human-unique Siglec-12, -14 and -16 suggests that the selection pressure is ongoing. [29]

As Siglecs feature distinct binding preferences for the sialic acid and its modifications, several attempts have been made to chemically modify natural sialic acid ligands and eventually led to the creation of sialic acid mimetics (SAMs) with enhanced binding capacity and selectivity towards Siglecs. [31]

Synthesis

SAMs can be used to target Siglecs and modulate Siglec-expressing cells by modifying the sialic acid backbone at various positions, from C-2 to C-9. [31] [32] [33] The carboxylic acid, however, must be left intact. [31] The first attempts were made to develop high-affinity sialic acid mimetics for Siglec-2, which led to the discovery that increased binding affinity came hydrogen bonding and lipophilic interactions between SAMs and Siglec-2. [31] Several separate modifications have been made at the C-2, C-5 and C-9 positions, leading Mesch et al. to hypothesizing that the simultaneous modification at all three positions could lead to optimization of binding. [34]

Success in drastically enhanced binding of SAMs to Siglec 2 suggests that a similar approach can work on other members of the family. Some modifications have included an additional simultaneous modification at the C-4 position on the sialic acid backbone. [31] The development of (copper) I-catalyzed azide alkyne cycloaddition (CuAAC) click chemistry has expedited the identification of new SAMs and allowed for the creation of novel SAMs with high binding to Siglec-3, -5, -6, -7 and -10. [35] As of 2017, SAMs for most Siglecs have been reported, except for Siglec -6, -8, -11, -14, -15 and -16. [31]

Clustering of receptors and high-avidity binding, collectively known as multivalent binding, can enhance the effectiveness of SAMs in human body. Currently, advancements in glycoengineering have made use of SAM-decorated nanoparticles, SAM-decorated polymers and on-cell synthesis of SAMs to present SAMs to Siglecs. [31] Liposomes crosslinked with SAMs also have been shown to aid in presenting antigens to antigen-presenting cells via the Siglec-1 or -7 pathways. [36] Moreover, human cells, engineered with sialic acids carrying Ac5NeuNPoc incorporated into its sialoglycans and 3-bromo-benzyl azide, showed hyperactivity towards Siglec-2. [31] [37]

Related Research Articles

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 and 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.

Fc receptor Protein

A Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

CD22

CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that prevents the overactivation of the immune system and the development of autoimmune diseases.

Galectin

Galectins are a class of proteins that bind specifically to β-galactoside sugars, such as N-acetyllactosamine, which can be bound to proteins by either N-linked or O-linked glycosylation. They are also termed S-type lectins due to their dependency on disulphide bonds for stability and carbohydrate binding. There have been about 15 galectins discovered in mammals, encoded by the LGALS genes, which are numbered in a consecutive manner. Only galectin-1, -2, -3, -4, -7, -7B, -8, -9, -9B, 9C, -10, -12, -13, -14, and -16 have been identified in humans. Galectin-5 and -6 are found in rodents, whereas galectin-11 and -15 are uniquely found in sheep and goats. Members of the galectin family have also been discovered in other mammals, birds, amphibians, fish, nematodes, sponges, and some fungi. Unlike the majority of lectins they are not membrane bound, but soluble proteins with both intra- and extracellular functions. They have distinct but overlapping distributions but found primarily in the cytosol, nucleus, extracellular matrix or in circulation. Although many galectins must be secreted, they do not have a typical signal peptide required for classical secretion. The mechanism and reason for this non-classical secretion pathway is unknown.

Sialoadhesin

Sialoadhesin is a cell adhesion molecule found on the surface of macrophages. It is found in especially high amounts on macrophages of the spleen, liver, lymph node, bone marrow, colon, and lungs. Also, in patients suffering from rheumatoid arthritis, the protein has been found in great amounts on macrophages of the affected tissues. It is defined as an I-type lectin, since it contains 17 immunoglobulin (Ig) domains, and thus also belongs to the immunoglobulin superfamily (IgSF). Sialoadhesin binds to certain molecules called sialic acids. During this binding process a salt bridge (protein) is formed between a highly conserved arginine residue and the carboxylate group of the sialic acid. Since sialoadhesin binds sialic acids with its N-terminal IgV-domain, it is also a member of the SIGLEC family. Alternate names for sialoadhesin include siglec-1 and CD169.

CD33

CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.

An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family found on immune cells. These immune cells include T cells, B cells, NK cells, dendritic cells, macrophages and mast cells. ITIMs have similar structures of S/I/V/LxYxxI/V/L, where x is any amino acid, Y is a tyrosine residue that can be phosphorylated, S is the amino acide Serine, I is the amino acid Isoleucine, and V is the amino acid Valine. ITIMs recruit SH2 domain-containing phosphatases, which inhibit cellular activation. ITIM-containing receptors often serve to target Immunoreceptor tyrosine-based activation motif(ITAM)-containing receptors, resulting in an innate inhibition mechanism within cells. ITIM bearing receptors have important role in regulation of immune system allowing negative regulation at different levels of the immune response.

The mannose receptor is a C-type lectin primarily present on the surface of macrophages, immature dendritic cells and liver sinusoidal endothelial cells, but is also expressed on the surface of skin cells such as human dermal fibroblasts and keratinocytes. It is the first member of a family of endocytic receptors that includes Endo180 (CD280), M-type PLA2R, and DEC-205 (CD205).

CD69

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.

CLEC7A

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.

SIGLEC7

Sialic acid-binding Ig-like lectin 7 is a protein that in humans is encoded by the SIGLEC7 gene. SIGLEC7 has also been designated as CD328.

Sialic acid-binding Ig-like lectin 12

Sialic acid-binding Ig-like lectin 12, or Siglec-XII, is a protein that in humans, is encoded by the SIGLEC12 gene.

SIGLEC5

Sialic acid-binding Ig-like lectin 5 is a protein that in humans is encoded by the SIGLEC5 gene. SIGLEC5 has also been designated CD170.

SIGLEC9

Sialic acid-binding Ig-like lectin 9 is a protein that in humans is encoded by the SIGLEC9 gene.

SIGLEC8

Sialic acid-binding Ig-like lectin 8 is a protein that in humans is encoded by the SIGLEC8 gene. This gene is located on chromosome 19q13.4, about 330 kb downstream of the SIGLEC9 gene. Within the siglec family of transmembrane proteins, Siglec-8 belongs to the CD33-related siglec subfamily, a subfamily that has undergone rapid evolution.

SIGLEC10

Sialic acid-binding Ig-like lectin 10 is a protein that in humans is encoded by the SIGLEC10 gene. Siglec-G is often referred to as the murine paralog of human Siglec-10

The following outline is provided as an overview of and topical guide to immunology:

Killer activation receptor

Killer Activation Receptors (KARs) are receptors expressed on the plasmatic membrane of Natural Killer cells. KARs work together with inhibitory receptors, which inactivate them in order to regulate the NK cells functions on hosted or transformed cells. These two kinds of specific receptors have some morphological features in common, such as being transmembrane proteins. The similarities are specially found in the extracellular domains and, the differences tend to be in the intracellular domains. KARs and KIRs can have tyrosine containing activatory or inhibitory motifs in the intracellular part of the receptor molecule.

CD94/NKG2 is a family of C-type lectin receptors which are expressed predominantly on the surface of NK cells and a subset of CD8+ T-lymphocyte. These receptors stimulate or inhibit cytotoxic activity of NK cells, therefore they are divided into activating and inhibitory receptors according to their function. CD94/NKG2 recognize nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse).

Immune checkpoint Regulators of the immune system

Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.

References

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