ArticleThe Journal of biological chemistry2016
Asn347 Glycosylation of Corticosteroid-binding Globulin Fine-tunes the Host Immune Response by Modulating Proteolysis by Pseudomonas aeruginosa and Neutrophil Elastase.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- TS3 Asn347 corticosteroid-binding globulin (CBG) glycoform deficiency is associated with mortality in human septic shock.Journal of the Endocrine Society · 2026Article
- Harnessing native corticosteroid-binding globulin to treat life-threatening septic shock.Endocrinology · 2026Article
- RCL glycosylation of serum corticosteroid-binding globulin: implications in cortisol delivery and septic shock.Glycobiology · 2025Article
- The NE/AAT/CBG axis regulates adipose tissue glucocorticoid exposure.Nature communications · 2025Article
- BetaJACC. Basic to translational science · 2023Article
- The Nasal Innate Immune Proteome After Saline Irrigation: A Pilot Study in Healthy Individuals.American journal of rhinology & allergy · 2023Article
- Redox and proteolytic regulation of cardiomyocyte βFrontiers in immunology · 2023Article
- Towards structure-focused glycoproteomics.Biochemical Society transactions · 2021Review
- Pyrexia and acidosis act independently of neutrophil elastase reactive center loop cleavage to effect cortisol release from corticosteroid-binding globulin.Protein science : a publication of the Protein Society · 2020Article
- The Functional Power of the Human Milk Proteome.Nutrients · 2019Review
- N-Glycosylation influences human corticosteroid-binding globulin measurements.Endocrine connections · 2019Article
- Structural basis for the specificity of renin-mediated angiotensinogen cleavage.The Journal of biological chemistry · 2019Article
- Neutrophil elastase-cleaved corticosteroid-binding globulin is absent in human plasma.The Journal of endocrinology · 2019Article
- Crystal structure of highly glycosylated human leukocyte elastase in complex with an S2' site binding inhibitor.Acta crystallographica. Section F, Structural biology communications · 2018Article
- Functional implications of corticosteroid-binding globulinJournal of molecular endocrinology · 2018Article
- Paucimannose-RichMolecular & cellular proteomics : MCP · 2017Article
- Hyper-truncated Asn355- and Asn391-glycans modulate the activity of neutrophil granule myeloperoxidase.The Journal of biological chemistryArticle
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Corticosteroid-binding globulin (CBG) delivers anti-inflammatory cortisol to inflamed tissues upon elastase-based proteolysis of the exposed reactive center loop (RCL). However, the molecular mechanisms that regulate the RCL proteolysis by co-existing host and bacterial elastases in inflamed/infected tissues remain unknown. We document that RCL-localized Asn(347) glycosylation fine-tunes the RCL cleavage rate by human neutrophil elastase (NE) and Pseudomonas aeruginosa elastase (PAE) by different mechanisms. NE- and PAE-generated fragments of native and exoglycosidase-treated blood-derived CBG of healthy individuals were monitored by gel electrophoresis and LC-MS/MS to determine the cleavage site(s) and Asn(347) glycosylation as a function of digestion time. The site-specific (Val(344)-Thr(345)) and rapid (seconds to minutes) NE-based RCL proteolysis was significantly antagonized by several volume-enhancing Asn(347) glycan features (i.e. occupancy, triantennary GlcNAc branching, and α1,6-fucosylation) and augmented by Asn(347) NeuAc-type sialylation (all p < 0.05). In contrast, the inefficient (minutes to hours) PAE-based RCL cleavage, which occurred equally well at Thr(345)-Leu(346) and Asn(347)-Leu(348), was abolished by the presence of Asn(347) glycosylation but was enhanced by sialoglycans on neighboring CBG N-sites. Molecular dynamics simulations of various Asn(347) glycoforms of uncleaved CBG indicated that multiple Asn(347) glycan features are modulating the RCL digestion efficiencies by NE/PAE. Finally, high concentrations of cortisol showed weak bacteriostatic effects toward virulent P. aeruginosa, which may explain the low RCL potency of the abundantly secreted PAE during host infection. In conclusion, site-specific CBG N-glycosylation regulates the bioavailability of cortisol in inflamed environments by fine-tuning the RCL proteolysis by endogenous and exogenous elastases. This study offers new molecular insight into host- and pathogen-based manipulation of the human immune system.
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