Abstract
The recognition of oligomannose-type glycans in innate and adaptive immunity is elusive due to multiple closely related isomeric glycan structures. To explore the functions of oligomannoses, we developed a multifaceted approach combining mass spectrometry assignments of oligomannose substructures and the development of a comprehensive oligomannose microarray. This defined microarray encompasses both linear and branched glycans, varying in linkages, branching patterns, and phosphorylation status. With this resource, we identified unique recognition of oligomannose motifs by innate immune receptors, including DC-SIGN, L-SIGN, Dectin-2, and Langerin, broadly neutralizing antibodies against HIV gp120, N-acetylglucosamine-1-phosphotransferase, and the bacterial adhesin FimH. The results demonstrate that each protein exhibits a unique specificity to oligomannose motifs and suggest the potential to rationally design inhibitors to selectively block these protein-glycan interactions.
Highlights
Oligomannose-type glycans are key components of eukaryotic cells, prokaryotic cells, and many viruses such as HIV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3,4,5]
The results presented here illustrate the unique glycan-binding specificities of C-type lectin receptors (CLRs), bacterial adhesin FimH, and HIV broadly neutralizing antibodies (bNAbs) toward oligomannose isomers
These new insights were enabled by the development of a comprehensive and well-defined oligomannose library encompassing closely related oligomannose isomers on the basis of a robust ESI-higher-energy collisional dissociation (HCD)-MS/MS structural characterization method
Summary
Oligomannose-type glycans are key components of eukaryotic cells, prokaryotic cells, and many viruses such as HIV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3,4,5]. In addition to playing a key structural role, oligomannoses have profound biological functions in maintaining cellular homeostasis. Oligomannoses on yeast and microorganisms, on the other hand, are pathogen-associated molecular patterns (PAMPs), which are recognized by a variety of host innate immune receptors including C-type lectin receptors (CLRs), such as DC-SIGN, L-SIGN, Dectin-2, and Langerin [12, 13]. Such interaction could promote endocytosis of the pathogens and production of cytokines and chemokines, leading to the activation of adaptive immunity. Despite being a key mediator in these immune recognition events, the precise oligomannose structures important for each interaction have not been fully elucidated
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