Abstract
While neutrophils are critical first-responders of the immune system, they also cause tissue damage and act in a variety of autoimmune diseases. Many neutrophil proteins are N-glycosylated, a post-translational modification that may affect, among others, enzymatic activity, receptor interaction, and protein backbone accessibility. So far, a handful neutrophil proteins were reported to be decorated with atypical small glycans (paucimannose and smaller) and phosphomannosylated glycans. To elucidate the occurrence of these atypical glycoforms across the neutrophil proteome, we performed LC-MS/MS-based (glyco)proteomics of pooled neutrophils from healthy donors, obtaining site-specific N-glycan characterisation of >200 glycoproteins. We found that glycoproteins that are typically membrane-bound to be mostly decorated with high-mannose/complex N-glycans, while secreted proteins mainly harboured complex N-glycans. In contrast, proteins inferred to originate from azurophilic granules carried distinct and abundant paucimannosylation, asymmetric/hybrid glycans, and glycan phosphomannosylation. As these same proteins are often autoantigenic, uncovering their atypical glycosylation characteristics is an important step towards understanding autoimmune disease and improving treatment.
Highlights
While neutrophils are critical first-responders of the immune system, they cause tissue damage and act in a variety of autoimmune diseases
While neutrophils are some of the most critical first responders of our immune system, these cells can be responsible for much tissue damage partly through the production/secretion of proteins that end up being targets of autoantibodies[9,10,11]
Neutrophil protein post-translational modifications (PTMs) remains an understudied subject, even while these may have a significant influence on enzymatic activity, interaction with other proteins, inhibitors and scavengers, and the overall accessibility of immunogenic epitopes
Summary
While neutrophils are critical first-responders of the immune system, they cause tissue damage and act in a variety of autoimmune diseases. Proteins inferred to originate from azurophilic granules carried distinct and abundant paucimannosylation, asymmetric/hybrid glycans, and glycan phosphomannosylation As these same proteins are often autoantigenic, uncovering their atypical glycosylation characteristics is an important step towards understanding autoimmune disease and improving treatment. 1234567890():,; Neutrophils are the most abundant white blood cells and play a critical role in the immune system, being some of the first responders to migrate towards sites of inflammation and perform local antimicrobial functions[1,2] Underlining their importance, neutrophils are produced in massive quantities and end up filling more than half the population of leucocytes in human blood—even though the individual cells are relatively short-lived, with lifetimes in the order of days[3]. Next to exploring the overall glycosylation of neutrophil proteins in a site-specific manner, we aimed to confirm their atypical glycan characteristics and to elucidate whether this could be attributed to certain protein subsets
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