Glycosylation is one of the most important protein post-translational modifications in organisms, occurring in 50%-70% of proteins in cells. It is associated with many diseases as it can affect essential life activities, such as cell recognition, differentiation, adhesion, signal transduction, and immune response. Immune diseases, congenital sugar defects, and dozens of genetic diseases, as well as cancers, are linked with abnormal glycosylation or lack of glycosidase.
In terms of structure, the glycosylated modification has macroscopic (Multiple glycosylation sites on a protein, and even different types of glycosylation sites) and microcosmic heterogeneity (Different types of polysaccharides can be attached to the same glycosylation site). Glycosylation is more complex than other modifications.
According to different glycosidic linkages, glycosylation can be divided into N-glycosylation (which can be subdivided into high mannitose, complex, and heterozygous types), O-glycosylation, C-glycosylation, and glycosylphosphatidylinositol (GPI), each has different functions. Among which, N- glycosylation is the most studied, followed by O- glycosylation.
N-glycosylation is a co-translation or post-translational modification of nascent peptide chains. The sugar chain is connected to the free -NH2 group of the specific asparagine (N-X-S/T, X≠P) in the nascent peptide chain. The N-glycosylation process happens in the endoplasmic reticulum and Golgi apparatus. N-glycosylation modification mainly includes N-sugar synthesis, transfer, and modification. N-sugar synthesis and transfer are carried out in the endoplasmic reticulum and the modification in both the endoplasmic reticulum and the Golgi apparatus. In addition, N-glycosylation modification also differs in plants and mammals.
N-glycosylation modification is important in protein folding, functional positioning, and intracellular transport. In mammals, N-glycosylation plays a part in regulating embryonic development, cancer occurrence and development, and immune defense. In plants, N-glycosylation is of great significance to many physiological processes such as cell wall formation, reproductive development, and resistance to pathogen invasion.
Study of N- glycosylation in immune system and tumor
Protein glycosylation or glycan affects the structure and function of immune cells and immune molecules, and affects the body’s response to antigens. Most of the molecules in the immune system are glycoproteins, such as immunoglobulins, cytokines, complement, differentiation antigens, adhesion molecules and MHC molecules. Glycosylation of immune system molecules has been explored for disease marker research.
Glycosylation can regulate tumor proliferation, invasion, metastasis, and angiogenesis. Abnormal glycosylation is often considered a sign of cancer. Most tumor markers approved by the FDA are glycoprotein or glycan antigens.
The degree of N-glycan branching can affect the proliferation of tumor cells by regulating the activity and signal transduction of growth factor receptors (EGFR, FGFR, PDGF, etc.).
Tumor invasion and metastasis are also related to glycosylation in various ways. Cancer cells usually have high levels of sialylation. Increasing sialyation will also increase the local negative charge, thereby physically destroying cell adhesion and promoting detachment from the tumor mass through electrostatic repulsion to enhance tumor cell invasion.
In general, changes in genetic, epigenetic, metabolic, inflammatory and microenvironmental mechanisms during cancer progression are closely related to changes in glycosylation.
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