Review Article | Published:

Glycosylation in health and disease

Abstract

The glycome describes the complete repertoire of glycoconjugates composed of carbohydrate chains, or glycans, that are covalently linked to lipid or protein molecules. Glycoconjugates are formed through a process called glycosylation and can differ in their glycan sequences, the connections between them and their length. Glycoconjugate synthesis is a dynamic process that depends on the local milieu of enzymes, sugar precursors and organelle structures as well as the cell types involved and cellular signals. Studies of rare genetic disorders that affect glycosylation first highlighted the biological importance of the glycome, and technological advances have improved our understanding of its heterogeneity and complexity. Researchers can now routinely assess how the secreted and cell-surface glycomes reflect overall cellular status in health and disease. In fact, changes in glycosylation can modulate inflammatory responses, enable viral immune escape, promote cancer cell metastasis or regulate apoptosis; the composition of the glycome also affects kidney function in health and disease. New insights into the structure and function of the glycome can now be applied to therapy development and could improve our ability to fine-tune immunological responses and inflammation, optimize the performance of therapeutic antibodies and boost immune responses to cancer. These examples illustrate the potential of the emerging field of ‘glycomedicine’.

Key points

  • Glycosylation is critical for physiological and pathological cellular functions; advances in analytical techniques have driven progression in the field of glycobiology over the past decade.

  • Congenital disorders of glycosylation have provided considerable insight into basic mechanisms underlying the associations of specific glycoconjugates with disease phenotypes.

  • Interactions between immune cells that are mediated by cell surface molecules and drive cellular activation are regulated by the glycosylation motifs of membrane-bound glycoconjugates and their binding to sugar-specific receptors.

  • Cancers often exhibit oncofetal phenotypes that are reflected in the nature of their glycoconjugates; these changes in glycosylation drive metastatic properties, inhibition of apoptosis and resistance to chemotherapy.

  • The pathogenesis of many autoimmune diseases, such as immunoglobulin A (IgA) nephropathy, systemic lupus erythematosus and inflammatory bowel disease, involves abnormal glycosylation of one or more glycoproteins; diabetes involves abnormal O-linked N-acetylglucosamine-mediated signalling and enhanced glycation of multiple proteins.

  • Immunoglobulin glycosylation controls the effector functions of antibodies, which creates opportunities for the therapeutic application of glycoengineering.

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Competing interests

J.N. and M.B.R. are co-founders of Reliant Glycosciences, LLC. The other authors declare no competing interests.

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Acknowledgements

The authors’ work was supported in part by grants from the US National Institutes of Health (DK106341, DK078244, GM098539, DK082753, DK109599, DK079337 and DK105124) and a gift from the IGA Nephropathy Foundation of America. The authors apologize to their colleagues in the field whose work is not adequately discussed or cited in this Review owing to space limitations.

Reviewer information

Nature Reviews Nephrology thanks M. Wild and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

All authors researched data for the article, made substantial contributions to the discussion of content and wrote, reviewed and edited the manuscript before submission.

Competing interests

J.N. and M.B.R. are co-founders of Reliant Glycosciences, LLC. The other authors declare no competing interests.

Correspondence to Matthew B. Renfrow or Jan Novak.

Supplementary information

Supplementary Information

Glossary

Glycans

Saccharides or sugar chains that can be free or attached to proteins or lipids to form simple or complex glycoconjugates.

N-linked glycans

Branched protein glycans attached through a nitrogen atom of Asn residues at Asn-X-Ser/Thr motifs.

O-linked glycans

Diverse protein glycans typically attached to an oxygen atom of Ser or Thr residues.

Glycosaminoglycans

Long unbranched polysaccharides made of repeating disaccharide units often attached to proteins.

Glycosylphosphatidylinositol (GPI) anchors

Short glycolipids that link proteins to the cell membrane.

C-mannosylation

The attachment of an α-mannopyranosyl to the indole-C2 carbon of a Trp residue.

Glycosphingolipids

(GSLs). Sphingolipids with attached glycan moieties that exist in the cell membrane.

Glycosyltransferases

Enzymes that add glycans.

Glycosidases

Enzymes that remove glycans.

High-mannose N-glycan

A less-processed N-glycan with high mannose content.

Hybrid N-glycan

A partially processed N-glycan with mannose and one antenna containing N-acetylglucosamine.

Complex N-glycan

Processed N-glycan with two, three or four antennas and possibly with bisecting N-acetylglucosamine.

Basic core structures

For N-glycans, the basic core structure is a common pentasaccharide GlcNAc2Man3. For O-glycans, cores 1–4 are defined on the basis of the glycans attached to the initial N-acetylgalactosamine (GalNAc); for example, core 1 is GalNAc with β1,3-linked galactose.

Glycocalyx

A cell-surface layer of glycosaminoglycans, proteoglycans and glycoproteins that extends far from the cell membrane.

Activated sugar intermediates

Monosaccharides with high-energy donors attached, such as UDP-sugar, GDP-sugar or, in the case of sialic acid, CMP-sialic acid.

Dandy–Walker malformation

A brain malformation that occurs during embryonic development of the cerebellum (linked to movement, coordination, cognition and behaviour) and the fourth ventricle (which channels fluid from inside to around the outside of the brain).

Coloboma

An eye abnormality that occurs before birth and refers to missing pieces of tissue in structures that form the eye, such as the iris, retina, choroid or optic disc.

Multi-antennary N-glycans

N-linked glycans with multiple branching glycan structures (that is, three or more antennas).

J chain

Joining chain that links monomers of immunoglobulin A (IgA) or IgM to form polymeric IgA or polymeric IgM.

Monosialoganglioside

A ganglioside, which is a ceramide with a carbohydrate motif, that contains a single sialic acid.

Rheumatoid factor

Autoantibodies specific for the crystallizable fragment (Fc) part of immunoglobulin G (IgG) that are often present in the blood of patients with rheumatoid arthritis.

Condensation reaction

A reaction in which two molecules combine, releasing an H2O in the process.

Amadori rearrangement

A rearrangement reaction catalysed by a base or acid on the N-glycoside of an aldose to a 1-amino-1-deoxy-ketose.

Hexosamine biosynthesis

Nutrient-sensing pathway that converts fructose-6-phosphate to UDP-N-acetylgalactosamine.

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Fig. 1: Major types of glycosylation in humans.
Fig. 2: N-glycan biosynthesis in the secretory pathway.
Fig. 3: Functional impact of variable IgG Fc glycan composition.
Fig. 4: Structure and glycosylation of human IgA.
Fig. 5: ST6GalI and abnormal sialylation in cancer.
Fig. 6: Aberrant O-glycosylation in IgA nephropathy.
Fig. 7: Glycoconjugates and glomerular filtration.