Siglecs and Their Role in Immune System

Introduction of Siglecs

Sialic acid-binding Ig-like lectins are also called Siglecs, which are lectins that can specifically bind to sialic acid residues. they are mainly located on the cell surface of hematopoietic cells, but some other cells can also be expressed. They are type I lectins whose extracellular region contains a sialic acid-binding V-set Ig-like domain and 1-16 C2-set Ig-like domains at the N-terminus. The cytoplasmic tails of all Siglecs have one or more tyrosine residues within the potential signaling motif.

Carbohydrates are important elements in the regulation of biological signals. All eukaryotic cells are surrounded by proteoglycans, sphingolipids, and glycoproteins, and sugar residues on the cell surface are directly involved in the regulation of many key cellular processes. In vertebrates, most of these membrane glycans have Sialic Acid residues at their outermost positions. CD BioGlyco provides Sialic Acid Analysis Service and Custom Carbohydrate Synthesis binding Siglecs service for customers to study the functions of Siglecs. Glycosylation of Cell Membranes solution also can help customers to research sialic acid on membranes.

Fig.1 Structural features of Siglecs. (Crocker & Varki, 2001)

Introduction of Sialic Acids (Sias)

Sias are a family of nine-carbon sugars that are mainly expressed by vertebrates and some microbial pathogens. The sialic acid is usually located at the end of the sugar chain, and the carboxyl group in the axial (up) isomer is conventionally referred to as the α- form; When the hydroxyl group of C-2 is in the axial direction, it is said to be of the β- form. The first carbon atom on the sialic acid is carboxyl carbon. The remaining carbon atoms form a loop, including C-2 to C-6, and an outer loop side chain, including C-7, C-8, and C-9.

Fig.2 A schematic view of the structure of sialic acid. (Pillai, et al., 2012)

Siglecs Family

Based on sequence similarity and evolutionary conservation, Siglecs are classified into two major groups. All Siglecs consist of two distinct domains: the extracellular immunoglobulin (Ig) domains including variable (V) and constant (C2)-set domains, and a transmembrane domain.

Fig.3 The protein structures of the Siglec family from the UniProt protein database. (A) Protein structures determined using X-ray; (B) Protein structure by prediction. (Jiang, et al., 2022)

Role in Immune System

Siglec family members are specifically expressed in a variety of immune cells and induce strong inhibitory signaling when Siglecs bind sialic acid. The physiological processes Siglecs involve the initial activation, proliferation, and apoptosis of immune cells. The surface of tumor cells is often highly glycosylated and rich in sialic acids. Siglecs mediate cell-cell or pathogen-cell interactions by recognizing monosaccharide sialic acids (Sia) on the surface of tumor cells and play an important regulatory role in the immune response.

Because it regulates the balance between self and non-self recognition, it can mediate cell adhesion, cell signaling, and uptake of sialylated pathogens. In addition, Sia-Siglec is also involved in the capture and presentation of antigens by antigen-presenting cells and affects the function of antigen-presenting cells. In the process of immune activation, Siglecs counteract the overreactive immune response under immune stimulation through damage-associated molecular patterns (DAMPs), help the host to evade immunity, and may lead to tumor progression. Carbohydrate-Lectin Interactions and Disease-related Changes in Carbohydrates are promising research directions.

Applications

Nonimmune regulatory functions of Siglecs

• Siglecs induce apoptosis: An important function of D33-related Siglecs is to regulate cell growth and survival by inhibiting proliferation or inducing apoptosis. Siglec-3 is a prominent example.
• Siglecs promote tumor angiogenesis: Siglec-9 causes loss of expression of co-stimulatory and antigen-presenting molecules in tumor cells, leading to immune escape of tumor cells.

Immune regulation of Siglecs

• Siglecs mediate antigen presentation: Siglec-1 is mainly expressed on macrophages and plays an important role in macrophage antigen presentation.
• Siglecs inhibit the proliferation and activation of tumor-associated T cells: Siglecs play a role on the surface of T cells and mediate tumor immune escape.
• Siglecs inhibit the killing effect of natural killer (NK) cells: Targeting Siglec-7 and Siglec-9 has emerged as a novel therapeutic approach to enhance NK cell immune responses to cancer.
• Siglecs affect tumor-associated macrophage (TAM) function: Siglecs can affect the polarization of TAMs by secreting inhibitory cytokines and affect the phagocytosis of TAMs, thereby regulating tumor microenvironment (TME) and tumor progression.
• Siglecs weaken the killing effect of tumor-associated neutrophils: Siglec-9 induces SHP-1 recruitment and inhibits neutrophil killing of tumor cells.

Based on functions of Siglecs in biology, CD BioGlyco provides advanced analytical and synthetic services to provide high-quality support for research in this field. If you are interested in our services, please contact us, we have a team of excellent scientists for you.

References:

1. Crocker, P.R.; and Varki, A. Siglecs in the immune system. Immunology. 2001, 103(2): 37–145.
2. Jiang, K.Y.; et al. The intriguing roles of SIGLEC family members in the tumor microenvironment. Biomarker Research. 2022, 10(1).
3. Pillai, S.; et al. Siglecs and Immune Regulation. Annual Review of Immunology. 2012, 30(1): 357–392.
4. Ereño-Orbea, J.; et al. Molecular basis of human CD22 function and therapeutic targeting. Nature Communications. 2017, 8(1).