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KMID : 0620920180500100133
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Experimental & Molecular Medicine
2018 Volume.50 No. 10 p.133 ~ p.133
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Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice
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Wolters-Eisfeld Gerrit
Mercanoglu Baris
Hofmann Bianca T.
Wolpers Thomas
Schnabel Claudia
Harder Sonke
Steffen Pascal
Bachmann Kai
Steglich Babett
Schrader Jorg
Gagliani Nicola
Schluter Hartmut
Gungor Cenap
Izbicki Jakob R.
Wagener Christoph
Bockhorn Maximilian
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Abstract
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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.
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KEYWORD
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Metabolic diseases, Post-translational modifications
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