Biological and Technical Challenges in Unraveling the Role of N-Glycans in Immune Receptor Regulation

Abstract

N-glycosylation of membrane receptors is important for a wide variety of cellular processes. In the immune system, loss or alteration of receptor glycosylation can affect pathogen recognition, cell-cell interaction, and activation as well as migration. This is not only due to aberrant folding of the receptor, but also to altered lateral mobility or aggregation capacity. Despite increasing evidence of their biological relevance, glycosylation-dependent mechanisms of receptor regulation are hard to dissect at the molecular level. This is due to the intrinsic complexity of the glycosylation process and high diversity of glycan structures combined with the technical limitations of the current experimental tools. It is still challenging to precisely determine the localization and site-occupancy of glycosylation sites, glycan micro-and macro-heterogeneity at the individual receptor level as well as the biological function and specific interactome of receptor glycoforms. In addition, the tools available to manipulate N-glycans of a specific receptor are limited. Significant progress has however been made thanks to innovative approaches such as glycoproteomics, metabolic engineering, or chemoenzymatic labeling. By discussing examples of immune receptors involved in pathogen recognition, migration, antigen presentation, and cell signaling, this Mini Review will focus on the biological importance of N-glycosylation for receptor functions and highlight the technical challenges for examination and manipulation of receptor N-glycans.

The Abnormal Glycopatterns of Salivary Glycoproteins in Esophageal Squamous Cell Carcinoma Patients

“…The assembly of glycans is complex enzymatic progress catalyzed by a series of glycosyltransferases and glycosidases, which starts in the endoplasmic reticulum and matures in the Golgi apparatus ( Chao et al, 2020 ). As the most prevalent posttranslational modifications, glycosylation occurs on approximately 70% of human proteins and involves a wide range of biological processes, which could partially reflect human's physiological states ( Yu et al, 2020a ; de Haas et al, 2020 ). The alterations of glycosylation have been widely detected in various cancers and have shown a profound correlation with carcinogenesis ( Oliveira-Ferrer et al, 2017 ; Verhelst et al, 2020 ).…”

New Insights into Immunological Involvement in Congenital Disorders of Glycosylation (CDG) from a People-Centric Approach

“…Altered and/or inefficient vaccination responses have also been described [13,17]. From a biological standpoint, these clinical descriptions can be explained by the glycans' and glycosylation's central role in immune pathways, particularly in cell-cell interaction and pathogen recognition, as well as in immune response modulation [14,19]. However, as most CDG are associated with numerous anatomical and functional defects in various organs, including the immune system, the immune pathophysiology of these patients may be highly complex and multi-factorial.…”

Glycan and Its Role in Combating COVID-19

“…Immunoglobulin glycans impact the effect or functions of antibodies counting on the branching of N-glycans and/or the terminal sugars of N-glycans or O-glycans that embody brain sugar and sialic acid. In fact, immunoglobulin glycosylation can verify glycoform is pro-inflammatory, like Ig with galactose-deficient N-glycans, or anti-inflammatory drug, like Ig with sialylated N-glycans [17][18][19].…”

“…Though alternative SARS-CoV-2 proteins have foreseeable glycosylation sites (such as M-protein, E-protein), the bulk of experimental knowledge is presently accessible on the S-protein. This might be a trimeric protein that mediates viral adhesion through binding to the human angiotensin-converting accelerator two (hACE2) and conjointly interacts with the host immune defense [19,20].…”

“…Ultimately, this analysis shows that the RBM is often accessible once RBD is "up", whereas it's terribly well camouflaged when "down". This implies that the glycan shield of this vital domain is effectively paired with its "down-to-up" conformational amendment, allowing the RBM to transiently emerge from the glycan shield and bind to ACE2 receptors [16,19,20].…”