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RCL glycosylation of serum corticosteroid-binding globulin: implications in cortisol delivery and septic shock

ABSTRACT: Corticosteroid-binding globulin (CBG) is a serum glycoprotein that binds and delivers anti-inflammatory cortisol to inflammatory sites through neutrophil elastase (NE)-mediated proteolysis of an exposed reactive centre loop (RCL) on CBG. Timely and tissue-specific delivery of cortisol is critical to alleviate inflammation including in life-threatening septic shock conditions. Important for the cortisol delivery mechanism, which is facilitated by proteolytic cleavage of RCL of CBG and conformational changes to the protein, we recently identified novel O-glycosylation events within the RCL and documented their inhibition of RCL proteolysis (Chernykh et al., 2023). While these observations are of significance as they implicate RCL O-glycosylation as a potential regulator of cortisol delivery, the link to septic shock remains unexplored. To this end, we used mass spectrometry to profile the RCL O-glycosylation of CBG purified from serum of twelve septic shock patients. Serum CBG from all patients exhibited RCL O-glycosylation comprising both sialyl T and/or disialyl T (NeuAc1-2Gal1GalNAc1) O-glycan structures decorating exclusively the Thr342 site. Importantly, relative to less severe cases, individuals presenting with the most severe illness displayed elevated RCL O-glycosylation upon ICU admission, suggesting a previously unknown link to septic shock severity. Overall, we have elucidated RCL O-glycosylation events of serum CBG, which improve our understanding of molecular mechanisms governing the timely and tissue-specific delivery of cortisol to inflammatory sites. The work provides clues to molecular aberrations and disease mechanisms underpinning septic shock.

INSTRUMENT(S): Orbitrap Eclipse, Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

DISEASE(S): Septic Shock

SUBMITTER: Anastasia Chernykh

LAB HEAD: Morten Thaysen-Andersen

PROVIDER: PXD058963 | Pride | 2025-03-07

REPOSITORIES: Pride

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			Action	DRS
	20240805_AC_Patient12_Severe_PNG_eclipse.raw	Raw
	20240805_AC_Patient2_Moderate_PNG_eclipse.raw	Raw
	20240805_AC_Patient3_Moderate_PNG_eclipse.raw	Raw
	20240805_AC_Patient7_Severe_PNG_eclipse.raw	Raw
	20240805_AC_Patient8_Severe_PNG_eclipse.raw	Raw

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Project description:Goal of the experiment: To identify correlated genes, pathways and groups of patients with systemic inflammatory response syndrome and septic shock that is indicative of biologically important processes active in these patients. Background: We measured gene expression levels and profiles of children with systemic inflammatory response syndrome (SIRS) and septic shock as a means for discovering patient sub-groups and gene signatures that are active in disease-affected individuals and potentially in patients with poor outcomes. Methods: Microarray and bioinformatics analyses of 123 microarray chips representing whole blood derived RNA from controls, children with SIRS, and children with septic shock. Results: A discovery-based filtering approach was undertaken to identify genes whose expression levels were altered in patients with SIRS or septic shock. Clustering of these genes identified 3 Major and several minor sub-groups of patients with SIRS or septic shock. The three groups differed with respect to incidence of septic shock and trended toward differences in mortality. Statistical analyses demonstrated that 6,435 gene probes were differentially regulated between the three patient sub-groups (false discovery rate < 0.001%). Of these gene probes, 623 gene probes within 7 major gene ontologies accounted for the majority of group differentiation. Network analyses of these 623 gene probes demonstrated 5 major gene networks that were differentially expressed between the 3 groups. Statistical comparison of septic shock survivors and non-survivors identified one major gene network that was under expressed in a high fraction of the non-survivors and identified potential biomarkers for poor outcome. Conclusions: This is the first genome-level demonstration of pediatric patient sub-groups with SIRS and septic shock. The sub-groups differ clinically and differentially express 5 major gene networks. We have identified gene signatures and potential biomarkers associated with poor outcome in children with septic shock. These data represent a major advancement in our genome-level understanding of pediatric SIRS and septic shock. Keywords: Septic shock, SIRS, pediatrics, outcome, infection, inflammation

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RCL glycosylation of serum corticosteroid-binding globulin: implications in cortisol delivery and septic shock

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