Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice
| Autor: | Bianca T. Hofmann, Babett Steglich, Nicola Gagliani, Jörg Schrader, Kai Bachmann, Hartmut Schlüter, Thomas Wolpers, Baris Mercanoglu, Christoph Wagener, Jakob R. Izbicki, Cenap Güngör, Sönke Harder, Claudia Schnabel, Pascal Steffen, Gerrit Wolters-Eisfeld, Maximilian Bockhorn |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Proteomics Glycosylation Proteome Clinical Biochemistry Tn antigen lcsh:Medicine Biochemistry Article Frameshift mutation lcsh:Biochemistry 03 medical and health sciences chemistry.chemical_compound Mice Insulin-Secreting Cells medicine Endocrine system Animals lcsh:QD415-436 Lipase Exocrine pancreatic insufficiency Molecular Biology Cells Cultured Mice Knockout biology lcsh:R medicine.disease Phenotype Pancreas Exocrine Cell biology Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry Diabetes Mellitus Type 2 biology.protein Molecular Medicine Pancreas Molecular Chaperones |
| Zdroj: | Experimental and Molecular Medicine, Vol 50, Iss 10, Pp 1-13 (2018) Experimental & Molecular Medicine |
| ISSN: | 2092-6413 1226-3613 |
| Popis: | Cosmc is ubiquitously expressed and acts as a specific molecular chaperone assisting the folding and stability of core 1 synthase. Thus, it plays a crucial role in the biosynthesis of O-linked glycosylation of proteins. Here, we show that ablation of Cosmc in the exocrine pancreas of mice causes expression of truncated O-glycans (Tn antigen), resulting in exocrine pancreatic insufficiency with decreased activities of digestive enzymes and diabetes. To understand the molecular causes of the pleiotropic phenotype, we used Vicia villosa agglutinin to enrich Tn antigen-modified proteins from Cosmc-KO pancreatic lysates and performed a proteomic analysis. Interestingly, a variety of proteins were identified, of which bile salt-activated lipase (also denoted carboxyl-ester lipase, Cel) was the most abundant. In humans, frameshift mutations in CEL cause maturity-onset diabetes of the young type 8 (MODY8), a monogenic syndrome of diabetes and pancreatic exocrine dysfunction. Here, we provide data suggesting that differentially O-glycosylated Cel could negatively affect beta cell function. Taken together, our findings demonstrate the importance of correct O-glycan formation for normal exocrine and endocrine pancreatic function, implying that aberrant O-glycans might be relevant for pathogenic mechanisms of the pancreas. Pancreatic disorders: when protein modification misfires Reduced levels of a protein called Cosmc in the pancreas may lead to pancreatic disorders and a rare form of diabetes. Disruption to glycosylation, the process by which carbohydrates are added to proteins, can have significant knock-on effects for cellular functioning. Gerrit Wolters-Eisfeld at the University Medical Center Hamburg-Eppendorf, Germany, and co-workers used mouse models to demonstrate the importance of correct formation of one type of carbohydrate, O-glycans, for normal pancreatic function. The team generated mice without Cosmc, a molecule that assists with O-glycosylation. Loss of Cosmc in the pancreas resulted in shortened O-glycans and pancreatic insufficiency. However, one protein called Cel was modified in abundance; this may be further bad news because mutations in Cel are linked to the onset of a rare form of diabetes. |
| Databáze: | OpenAIRE |
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