An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology [Internet]. 4th edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2022. doi: 10.1101/glycobiology.4e.41
Glycans mediate or modulate numerous physiologic functions. This brief chapter focuses on vertebrate physiology (predominantly human), providing physiologists and physicians an overview of glycan impacts on organ system functions. Pathological aspects of glycan biosynthesis and degradation are discussed elsewhere. Given the breadth of physiologic functions of glycans, the individual sections highlight just a few representative examples, and listings are necessarily incomplete.
Glycans and glycan-binding proteins are important for both male and female reproduction. Studies in fish, frogs, and mammals indicate that glycans are involved in multiple steps in the process of fertilization (Chapter 27). In animals with internal fertilization, glycan-dependent recognition events occur during sperm interactions with reproductive tract mucins, in sperm–fallopian tube interactions, in sperm–ova binding within the fallopian tubes, and during implantation of the early embryo. Glycosylation-deficient male mice are sometimes infertile or subfertile. Following birth, mammals produce milk containing an array of glycoproteins and a complex mixture of species-specific milk oligosaccharides (Chapter 14).
Genetic modifications that eliminate initial steps of major glycan synthetic pathways and of some monosaccharide biosynthetic pathways generally result in embryonic lethality, with one exception being deletion of individual genes needed for initiation of mucin O-GalNAc pathway, likely because of functional redundancy among the 20 different polypeptide:O-GalNAc transferases (Chapter 10). The causes of these lethal outcomes usually cannot be linked to specific glycoconjugates, but sometimes can be ascribed to a single mechanism such as the disruption of protein O-fucosylation, which impacts global Notch receptor signaling (Chapter 13). Conversely, loss of terminal glycan modifications are usually not embryonic-lethal, instead they have specific defects in some cell types. Elimination of glycosaminoglycans also causes developmental abnormalities, most likely because of their roles in modulating growth factor function and in setting up morphogen gradients (Chapter 17). Although the elimination of glycosaminoglycans causes systemic developmental abnormalities, elimination of some proteoglycan core proteins that carry these glycans can have tissue-specific consequences (Chapters 17, 25, and 26).
Given the significant role of glycans in development, many classic biomarkers of mammalian embryonic stem cells (ESCs), defined initially by monoclonal antibodies (MAbs), unsurprisingly turned out to be glycans. Many of these markers are species-specific. For example, stage-specific embryonic antigen-1 (SSEA-1), otherwise known as Lewis x (Lex) or CD15, is a principal marker of mouse ESCs but is not present on human ESCs. Instead, human ESCs and induced pluripotent stem cells express globosides SSEA-3 and SSEA-4, and MAbs also react with TRA-1-60 and TRA-1-81, which detect keratan sulfate–related antigens and, also, the tetrasaccharide motif Galβ1-3GlcNAcβ1-3Galβ1-4GlcNAc.
Glycans affect functions of all classes of blood cells. ABO blood group antigens on human erythrocytes are glycans, and successful blood transfusion requires compatibility of these antigens between donor and recipient (Chapter 14). Glycans on glycoproteins (e.g., integrin GPIIb/IIIa [CD41/CD61]) on the surfaces of circulating platelets play key roles in hemostasis. The “platelet count” (i.e., number of platelets in blood) is tightly controlled; a low count (thrombocytopenia) causes bleeding and a high count (thrombocytosis) predisposes to pathologic clotting (thrombosis). Platelet count is affected by genetic alterations in enzymes responsible for synthesis of sialic acid (e.g., GNE) or of lactosamine units (e.g., B4GALT1) by increasing platelet destruction or inhibiting platelet production, respectively. Platelet aging is linked to loss of platelet surface sialic acid and increased clearance via the hepatic Ashwell–Morell receptor (AMR) (Chapter 34). Infection and inflammation can also cause thrombocytopenia because of human or microbial neuraminidases that render platelets available for AMR clearance. Selectins and their glycosylated ligands (Chapter 34) play critical roles in mediating the trafficking of hematopoietic stem cells into the marrow (a process critical for the success of hematopoietic stem cell transplantation) and of extravasation of leukocytes from the bloodstream into tissues. In each case, the ability of the circulating cells to engage target tissue endothelial beds depends on their expression of the tetrasaccharide, known as sialylated Lewis x (Slex) or CD15s, the canonical minimal binding determinant for selectins, found on N- and O-glycans and glycolipids. Leukocyte deficiency of SLex expression results in decreased extravasation with concomitant increased risk of infections. Alternatively, enforced expression of SLex via glycoengineering of stem cell surfaces, or of subsets of leukocytes, can promote their delivery to inflammatory sites and thereby enhance tissue regeneration or immunologic functions, respectively. Further information regarding the impact of selectin receptor/ligand interactions in hematologic disease is presented in Chapter 46.
Nearly all proteins in plasma are N-glycosylated for stability in circulation and their optimal function. Patients with N-glycosylation defects often have insufficient levels of coagulation factors such as antithrombin III and proteins C and S, because of instability and/or accelerated clearance (Chapter 45). The O-fucose glycans on Notch receptors regulate hematopoiesis and the hematopoietic stem cell niche (Chapter 13).
In addition to SLex, other glycan moieties on N- and O-glycans of certain glycoproteins affect differentiation, adhesion, and survival of leukocytes (Chapters 36 and 45). Signaling in leukocytes is also regulated by Siglecs, which recognize sialic acid–containing ligands as “self-associated molecular patterns” (SAMPs; Chapter 35), and O-fucose glycans on Notch receptors regulate many cell differentiation processes, including development of T cells in the thymus (Chapter 13). Galectins (Chapter 36) play key roles in immune cell activation and function, as do C-type lectins such as dendritic cell–specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on antigen-presenting cells (Chapter 34). Glycans are critical components of many antigens and may determine how epitopes are presented (e.g., presentation of glycolipid antigens by CD1a-positive lymphocytes and other antigen-presenting cells). Sialylated N-glycans in the IgG Fc domain play critical roles in antibody effector functions, and modulation of fucosylation and/or N-glycan display at Asn297 of human IgG regulates antibody-dependent cell-mediated cytotoxicity (ADCC) and complement activation.
Hyaluronan has a critical role in heart development (Chapter 16), and glycosaminoglycans modulate angiogenesis, in part because they bind growth factors such as vascular endothelial growth factor and fibroblast growth factor (Chapter 17). The structural integrity of the walls of blood vessels is thought to depend on glycans, including a high density of sialic acids at the luminal surface of endothelial cells, as well as glycosaminoglycans within the basement membrane underlying endothelial cells. Cardiac muscle integrity and optimal cardiovascular function depend on various glycans.
The luminal surface of epithelial cells in the upper and lower airways are covered by a dense and complex array of mostly O-glycosylated mucins (Chapter 10) secreted by goblet cells and submucosal glands. Structural glycoproteins, glycolipids, and secreted mucin molecules form barriers that maintain epithelial surface hydration and protect against physical and microbial invasion. Embryonic stem cells lacking complex N-glycans cannot properly organize the bronchial epithelium. N-glycans are also important for healthy lung function, as mice lacking the core α1-6-linked fucose of N-glycans develop emphysema-like symptoms caused by overexpression of matrix metalloproteinases that degrade the lung tissue; this may result from aberrant transforming growth factor-β1 signaling through its misglycosylated receptor. Gene knockouts of individual mucin polypeptides show overlapping functions. Mice lacking O-fucose glycans in the lung do not generate secretory cells necessary for airway integrity.
O-GlcNAc on proteins of the nucleus and cytoplasm modulate insulin action, and aberrant O-GlcNAcylation is linked to hyperglycemia (Chapter 19). N-glycans may also play a role in type II diabetes, as mice that cannot synthesize triantennary N-glycans develop diabetes when fed a high-fat diet. This deficiency alters the single N-glycan on the GLUT2 glucose transporter on pancreatic islet cells, accelerating its endocytosis, leading to loss from the cell surface and poor response to insulin. N-glycans may also be important for the production of functional thyroid hormones (e.g., targeting of endocytosed thyroglobulin to lysosomes for conversion to T3 and T4 in the thyroid gland; Chapter 33). The plasma half-life of several pituitary glycoprotein hormones is regulated by the presence of N-glycans that contain an unusual sulfated GalNAc (Chapters 14 and 31), which controls hormone clearance in the liver. O-GalNAc glycosylation can regulate peptide hormones by affecting proteolytic cleavage, as exemplified by O-glycan loss in the phosphate regulating hormone FGF23 causing familial tumoral calcinosis in patients deficient in GalNAc-T3 (Chapter 10).
Glycosaminoglycans (Chapters 16 and 17) are required for normal development, organization, and structure of both the gums and teeth. Oral commensal organisms interact with each other or the host epithelium using glycan recognition. Salivary gland–generated mucins help protect the oral cavity by preventing bacterial biofilm formation on teeth (Chapters 10 and 42). However, mucin sialoglycans also provide binding sites for tooth cavity–facilitating bacteria.
Glycans physically separate the luminal contents of the gut from the cells by organizing the mucin barrier that helps block pathogens. However, the microbiome of the GI tract also contains microbial symbionts that maintain a complex physiologic equilibrium. Some organisms practice “glycan foraging” of host (Chapter 37) and help prevent invasion by pathogens such as Helicobacter species in the stomach and anaerobic bacteria in the colon (Chapters 37 and 42). Helicobactor pylori infection rarely occurs in the duodenum, in which unusual GlcNAcα(1-4)-terminated O-linked mucins are expressed. This “antimicrobial glycan” inhibits the synthesis of cholesteryl-glucoside, a major cell wall component. Heparan sulfate in the intestinal basement membrane acts as a permeability barrier, preventing protein loss from the plasma into the gut. O-fucose glycans in the small intestine regulate the balance of secretory and goblet cells necessary for intestinal development.
The liver synthesizes a large fraction of plasma proteins, and nearly all these proteins are heavily N-glycosylated, making hepatocytes a traditional cell type for studying the organization and function of the Golgi apparatus. Notably, acute phase reactants are glycoproteins, and variations in glycosylation patterns may reflect physiologic responses. Both hepatocytes and Kupffer cells in the liver have specific glycan-based recognition systems (e.g., the Ashwell–Morell receptor [AMR]) to clear unwanted circulating molecules (see Chapters 28, 31, 32, and 34 for more information on liver receptors). Heparan sulfate proteoglycans in the space of Disse between fenestrated endothelium and hepatocytes bind lipoproteins and aid in their clearance. Liver modification of bilirubin, hormones, and drugs with glucuronic acid (“glucuronidation”) increases the water solubility improving clearance in the bile and/or the urine (Chapter 5).
Heparan sulfate glycosaminoglycans (Chapter 17) and sialic acid residues (Chapter 15) on podocalyxin are needed for the filtering function of the glomerular basement membrane. In addition, reduced branching of complex N-glycans causes kidney pathology that may result from an autoimmune response. As in the pulmonary and gastrointestinal tracts, mucins with O-GalNAc glycans (Chapter 10) and proteoglycans with glycosaminoglycans provide a barrier function at the luminal surfaces of the ureters and bladder.
Glucosylceramide and related glycosphingolipids help maintain the barrier function of the skin. Hyaluronan and dermatan sulfate each help maintain the structure of the dermis and participate in wound repair. The endothelial selectin “E-selectin” (CD62E) (Chapter 34) is induced by tumor necrosis factor (TNF), interleukin-1 (IL-1), lipopolysaccharide (LPS), or trauma on postcapillary venules. However, it is constitutively expressed on microvessels of skin, where it recruits SLex-bearing leukocytes and assures dermal immunosurveillance (Chapter 46).
Proper adhesion of skeletal muscle to extracellular matrix laminin requires unique O-mannose glycans on the sarcolemmal glycoprotein α-dystroglycan (Chapter 27). Various defects in this pathway cause mild to severe muscular dystrophies in both humans and mice (Chapter 45). Glycan-related interactions can promote clustering of acetylcholine receptors at neuromuscular junctions. Sialylated glycans on ion transport proteins are important, and their loss impairs control of calcium fluxes into skeletal muscle cells. Normal formation and ossification of cartilage into bone requires many glycosaminoglycans, including hyaluronan and heparan, chondroitin, and keratan sulfates all in the appropriate amounts (Chapters 16 and 17).
The central nervous system has the highest amount and concentration of sialic acid–containing glycolipids (gangliosides; Chapter 11), and alterations in these glycans affect neurological function. O-GlcNAcylation in specific cells of the brain sense nutrients and regulate satiety. The unusual polysialic acid chains on NCAM (neural cell adhesion molecule) differentially modulate the plasticity of the nervous system during embryogenesis (Chapter 15). The dystroglycanopathies mentioned above also typically have cognitive and/or neurologic defects in addition to muscle dysfunction (Chapter 45). There are additional instances wherein specific glycans appear to inhibit nerve regeneration after injury. Recognition of certain sialylated glycolipids by myelin-associated glycoprotein inhibits neuronal sprouting following injury (Chapter 35), and similar inhibitory effects may be mediated by the glycosaminoglycan chondroitin sulfate (Chapter 17). In both instances, targeted degradation of the glycan in vivo (by local injection of sialidase or chondroitinase, respectively) stimulates neuronal growth and repair, meaning that they normally prevent neuronal regeneration. Mutant mice lacking some complex N-glycans and glycosaminoglycans reveal the importance of these molecules in the development and organization of the nervous system (Chapters 9 and 17). Fucosylated N-glycans appear to play a role in modulating various aspects of neural development and function. The great majority of patients with inherited glycosylation disorders also have cognitive and/or neurological abnormalities, but specific mechanisms are mostly unknown (Chapter 45).
The authors acknowledge contributions to previous versions of this chapter by Linda Baum and Victor Vacquier and appreciate helpful comments and suggestions from Ruth Siew and Hans Wandall.
Only a few references are given here. Please also see the citations at the ends of individual chapters referred to above.
The content of this book is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 Unported license. To view the terms and conditions of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
Your browsing activity is empty.
Activity recording is turned off.
See more...
