scholarly journals Terminal Epitope-Dependent Branch Preference of Siglecs Toward N-Glycans

2021 ◽  
Vol 8 ◽  
Author(s):  
Shuaishuai Wang ◽  
Congcong Chen ◽  
Minhui Guan ◽  
Ding Liu ◽  
Xiu-Feng Wan ◽  
...  
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Cell Signaling ◽  
Immune Cell ◽  
Glycan Microarray ◽  
New Information ◽  
Sialic Acid Binding ◽  
Complex Glycans ◽  
Complex Glycan

Siglecs are sialic acid–binding immunoglobulin-like lectins that play vital roles in immune cell signaling. Siglecs help the immune system distinguish between self and nonself through the recognition of glycan ligands. While the primary binding specificities of Siglecs are known to be divergent, their specificities for complex glycans remain unclear. Herein, we determined N-glycan binding profiles of a set of Siglecs by using a complex asymmetric N-glycan microarray. Our results showed that Siglecs had unique terminal epitope-dependent branch preference when recognizing asymmetric N-glycans. Specifically, human Siglec-3, -9, and -10 prefer the α1-3 branch when Siaα2-6Galβ1-4GlcNAc terminal epitope serves as the binding ligand but prefer the opposite α1-6 branch when Siaα2-3Galβ1-4GlcNAc epitope serves as the ligand. Interestingly, Siglec-10 exhibited dramatic binding divergence toward a pair of Neu5Ac-containing asymmetric N-glycan isomers, as well as their Neu5Gc-containing counterparts. This new information on complex glycan recognition by Siglecs provides insights into their biological roles and applications.

Siglecs as Immune Cell Checkpoints in Disease

2020 ◽  
Vol 38 (1) ◽  
pp. 365-395 ◽  
Author(s):  
Shiteng Duan ◽  
James C. Paulson
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Cell Signaling ◽  
Blood Cells ◽  
Immune Cell ◽  
White Blood Cells ◽  
Therapeutic Interventions ◽  
Cell Type ◽  
Cell Responses ◽  
Sialic Acid Binding

Sialic acid–binding immunoglobulin-type lectins (Siglecs) are expressed on the majority of white blood cells of the immune system and play critical roles in immune cell signaling. Through recognition of sialic acid–containing glycans as ligands, they help the immune system distinguish between self and nonself. Because of their restricted cell type expression and roles as checkpoints in immune cell responses in human diseases such as cancer, asthma, allergy, neurodegeneration, and autoimmune diseases they have gained attention as targets for therapeutic interventions. In this review we describe the Siglec family, its roles in regulation of immune cell signaling, current efforts to define its roles in disease processes, and approaches to target Siglecs for treatment of human disease.

scholarly journals Probing the binding specificities of human Siglecs by cell-based glycan arrays

2021 ◽  
Vol 118 (17) ◽  
pp. e2026102118
Author(s):  
Christian Büll ◽  
Rebecca Nason ◽  
Lingbo Sun ◽  
Julie Van Coillie ◽  
Daniel Madriz Sørensen ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Cell Surface ◽  
Immune Cell ◽  
Late Onset ◽  
Cell Types ◽  
Hek293 Cells ◽  
Cell Functions ◽  
Binding Epitope ◽  
Sialic Acid Binding ◽  
Complex Glycan

Siglecs are a family of sialic acid–binding receptors expressed by cells of the immune system and a few other cell types capable of modulating immune cell functions upon recognition of sialoglycan ligands. While human Siglecs primarily bind to sialic acid residues on diverse types of glycoproteins and glycolipids that constitute the sialome, their fine binding specificities for elaborated complex glycan structures and the contribution of the glycoconjugate and protein context for recognition of sialoglycans at the cell surface are not fully elucidated. Here, we generated a library of isogenic human HEK293 cells with combinatorial loss/gain of individual sialyltransferase genes and the introduction of sulfotransferases for display of the human sialome and to dissect Siglec interactions in the natural context of glycoconjugates at the cell surface. We found that Siglec-4/7/15 all have distinct binding preferences for sialylated GalNAc-type O-glycans but exhibit selectivity for patterns of O-glycans as presented on distinct protein sequences. We discovered that the sulfotransferase CHST1 drives sialoglycan binding of Siglec-3/8/7/15 and that sulfation can impact the preferences for binding to O-glycan patterns. In particular, the branched Neu5Acα2–3(6-O-sulfo)Galβ1–4GlcNAc (6′-Su-SLacNAc) epitope was discovered as the binding epitope for Siglec-3 (CD33) implicated in late-onset Alzheimer’s disease. The cell-based display of the human sialome provides a versatile discovery platform that enables dissection of the genetic and biosynthetic basis for the Siglec glycan interactome and other sialic acid–binding proteins.

scholarly journals High-dimensional immune-profiling in cancer: implications for immunotherapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000363 ◽  
Author(s):  
Samuel Chuah ◽  
Valerie Chew
Keyword(s):  
Immune System ◽  
Immune Cell ◽  
Positive Impact ◽  
Cell Types ◽  
High Dimensional ◽  
Host Immune System ◽  
Cancer Therapies ◽  
Quality Of Data ◽  
New Information ◽  
Immune Profiling

Immunotherapy is a rapidly growing field for cancer treatment. In contrast to conventional cancer therapies, immunotherapeutic strategies focus on reactivating the immune system to mount an antitumor response. Despite the encouraging outcome in clinical trials, a large proportion of patients still do not respond to treatment and many experience different degrees of immune-related adverse events. Furthermore, it is now increasingly appreciated that even many conventional cancer therapies such as radiotherapy could have a positive impact on the host immune system for better clinical response. Hence, there is a need to better understand tumor immunity in order to design immunotherapeutic strategies, especially evidence-based combination therapies, for improved clinical outcomes. With this aim, cancer research turned its attention to profiling the immune contexture of either the tumor microenvironment (TME) or peripheral blood to uncover mechanisms and biomarkers which might aid in precision immunotherapeutics. Conventional technologies used for this purpose were limited by the depth and dimensionality of the data. Advances in newer techniques have, however, greatly improved the breadth and depth, as well as the quantity and quality of data that can be obtained. The result of these advances is a wealth of new information and insights on how the TME could be affected by various immune cell-types, and how this might in turn impact the clinical outcome of cancer patients . We highlight herein some of the high-dimensional technologies currently employed in immune profiling in cancer and summarize the insights and potential benefits they could bring in designing better cancer immunotherapies.

scholarly journals Current Status on Therapeutic Molecules Targeting Siglec Receptors

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2691
Author(s):  
María Pia Lenza ◽  
Unai Atxabal ◽  
Iker Oyenarte ◽  
Jesús Jiménez-Barbero ◽  
June Ereño-Orbea
Keyword(s):  
Sialic Acid ◽  
Immune Cells ◽  
Immune Cell ◽  
Critical Role ◽  
Bispecific Antibodies ◽  
Current Status ◽  
Car T ◽  
Sialic Acid Binding ◽  
Therapeutic Molecules ◽  
Immunological Homeostasis

The sialic acid-binding immunoglobulin-type of lectins (Siglecs) are receptors that recognize sialic acid-containing glycans. In the majority of the cases, Siglecs are expressed on immune cells and play a critical role in regulating immune cell signaling. Over the years, it has been shown that the sialic acid-Siglec axis participates in immunological homeostasis, and that any imbalance can trigger different pathologies, such as autoimmune diseases or cancer. For all this, different therapeutics have been developed that bind to Siglecs, either based on antibodies or being smaller molecules. In this review, we briefly introduce the Siglec family and we compile a description of glycan-based molecules and antibody-based therapies (including CAR-T and bispecific antibodies) that have been designed to therapeutically targeting Siglecs.

scholarly journals Siglec-7 Undergoes a Major Conformational Change When Complexed with the α(2,8)-Disialylganglioside GT1b

2006 ◽  
Vol 281 (43) ◽  
pp. 32774-32783 ◽  
Author(s):  
Helen Attrill ◽  
Akihiro Imamura ◽  
Ritu S. Sharma ◽  
Makoto Kiso ◽  
Paul R. Crocker ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Immune System ◽  
Sialic Acid ◽  
Binding Site ◽  
Structural Data ◽  
Site Structure ◽  
Sialic Acid Binding ◽  
Structural Template ◽  
Polar Interactions ◽  
Ganglioside Gt1b

The siglecs are a group of mammalian sialic acid binding receptors expressed predominantly in the immune system. The CD33-related siglecs show complex recognition patterns for sialylated glycans. Siglec-7 shows a preference for α(2,8)-disialylated ligands and provides a structural template for studying the key interactions that drive this selectivity. We have co-crystallized Siglec-7 with a synthetic oligosaccharide corresponding to the α(2,8)-disialylated ganglioside GT1b. The crystal structure of the complex offers a first glimpse into how this important family of lectins binds the structurally diverse gangliosides. The structure reveals that the C-C′ loop, a region implicated in previous studies as driving siglec specificity, undergoes a dramatic conformational shift, allowing it to interact with the underlying neutral glycan core of the ganglioside. The structural data in combination with mutagenesis studies show that binding of the ganglioside is driven by extensive hydrophobic contacts together with key polar interactions and that the binding site structure is complementary to preferred solution conformations of GT1b.

scholarly journals Distinct Endocytic Mechanisms of CD22 (Siglec-2) and Siglec-F Reflect Roles in Cell Signaling and Innate Immunity

2007 ◽  
Vol 27 (16) ◽  
pp. 5699-5710 ◽  
Author(s):  
Hiroaki Tateno ◽  
Hongyi Li ◽  
Melissa J. Schur ◽  
Nicolai Bovin ◽  
Paul R. Crocker ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Sialic Acid ◽  
Cell Signaling ◽  
Immune Cells ◽  
Innate Immune System ◽  
Innate Immune ◽  
B Cell Signaling ◽  
Sialic Acid Binding ◽  
Adp Ribosylation Factor ◽  
Endocytic Pathways

ABSTRACT Sialic acid-binding immunoglobulin-like lectins (siglecs) are predominately expressed on immune cells. They are best known as regulators of cell signaling mediated by cytoplasmic tyrosine motifs and are increasingly recognized as receptors for pathogens that bear sialic acid-containing glycans. Most siglec proteins undergo endocytosis, an activity tied to their roles in cell signaling and innate immunity. Here, we investigate the endocytic pathways of two siglec proteins, CD22 (Siglec-2), a regulator of B-cell signaling, and mouse eosinophil Siglec-F, a member of the rapidly evolving CD33-related siglec subfamily that are expressed on cells of the innate immune system. CD22 exhibits hallmarks of clathrin-mediated endocytosis and traffics to recycling compartments, consistent with previous reports demonstrating its localization to clathrin domains. Like CD22, Siglec-F mediates endocytosis of anti-Siglec-F and sialoside ligands, a function requiring intact tyrosine-based motifs. In contrast, however, we find that Siglec-F endocytosis is clathrin and dynamin independent, requires ADP ribosylation factor 6, and traffics to lysosomes. The results suggest that these two siglec proteins have evolved distinct endocytic mechanisms consistent with roles in cell signaling and innate immunity.

scholarly journals Siglec Ligands

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1260
Author(s):  
Anabel Gonzalez-Gil ◽  
Ronald L. Schnaar
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Therapeutic Intervention ◽  
Binding Proteins ◽  
Cellular Responses ◽  
Cell Physiology ◽  
Molecular Pathways ◽  
Cell Surfaces ◽  
Sugar Moiety ◽  
Sialic Acid Binding

A dense and diverse array of glycans on glycoproteins and glycolipids decorate all cell surfaces. In vertebrates, many of these carry sialic acid, in a variety of linkages and glycan contexts, as their outermost sugar moiety. Among their functions, glycans engage complementary glycan binding proteins (lectins) to regulate cell physiology. Among the glycan binding proteins are the Siglecs, sialic acid binding immunoglobulin-like lectins. In humans, there are 14 Siglecs, most of which are expressed on overlapping subsets of immune system cells. Each Siglec engages distinct, endogenous sialylated glycans that initiate signaling programs and regulate cellular responses. Here, we explore the emerging science of Siglec ligands, including endogenous sialoglycoproteins and glycolipids and synthetic sialomimetics. Knowledge in this field promises to reveal new molecular pathways controlling cell physiology and new opportunities for therapeutic intervention.

scholarly journals Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunities

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 207 ◽  
Author(s):  
Emily Rodrigues ◽  
Matthew Macauley
Keyword(s):  
Sialic Acid ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Immune Cell ◽  
Cell Types ◽  
Functional Roles ◽  
Cell Responses ◽  
Disease Prognosis ◽  
Sialic Acid Binding ◽  
Cancer Types

Cell surface glycosylation is dynamic and often changes in response to cellular differentiation under physiological or pathophysiological conditions. Altered glycosylation on cancers cells is gaining attention due its wide-spread occurrence across a variety of cancer types and recent studies that have documented functional roles for aberrant glycosylation in driving cancer progression at various stages. One change in glycosylation that can correlate with cancer stage and disease prognosis is hypersialylation. Increased levels of sialic acid are pervasive in cancer and a growing body of evidence demonstrates how hypersialylation is advantageous to cancer cells, particularly from the perspective of modulating immune cell responses. Sialic acid-binding receptors, such as Siglecs and Selectins, are well-positioned to be exploited by cancer hypersialylation. Evidence is also mounting that Siglecs modulate key immune cell types in the tumor microenvironment, particularly those responsible for maintaining the appropriate inflammatory environment. From these studies have come new and innovative ways to block the effects of hypersialylation by directly reducing sialic acid on cancer cells or blocking interactions between sialic acid and Siglecs or Selectins. Here we review recent works examining how cancer cells become hypersialylated, how hypersialylation benefits cancer cells and tumors, and proposed therapies to abrogate hypersialylation of cancer.

New I-type lectins of the CD 33-related siglec subgroup identified through genomics

2002 ◽  
Vol 69 ◽  
pp. 83-94 ◽  
Author(s):  
Paul R. Crocker ◽  
Jiquan Zhang
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Immune Responses ◽  
Expression Patterns ◽  
Binding Properties ◽  
Immune Systems ◽  
Sialic Acid Binding ◽  
Ig Superfamily ◽  
Functional Screens ◽  
Signalling Motifs

Siglecs are sialic-acid-binding proteins of the Ig superfamily that are involved in cell–cell interactions and signalling. In recent years, several novel siglecs that are highly related to CD33/Siglec-2 have been identified through genomics and functional screens. In addition to their distinct sialic-acid-binding properties, most of these novel siglecs bear tyrosine-based signalling motifs that are typically found in inhibitory receptors of the immune system. The restricted expression patterns of CD33-related siglecs in the haemopoietic and immune systems suggests that they are involved in regulating leucocyte activation during inflammatory and immune responses.

New Trends in Anti-Cancer Therapy: Combining Conventional Chemotherapeutics with Novel Immunomodulators

2018 ◽  
Vol 25 (36) ◽  
pp. 4758-4784 ◽  
Author(s):  
Amy L. Wilson ◽  
Magdalena Plebanski ◽  
Andrew N. Stephens
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Immune System ◽  
Cancer Therapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Tumour Microenvironment ◽  
Immune Checkpoints ◽  
Tumour Regression ◽  
Cell Trafficking

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

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