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Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice

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Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice. / Wolters-Eisfeld, Gerrit; Mercanoglu, Baris; Hofmann, Bianca Thidahan; Wolpers, Thomas; Schnabel, Claudia; Harder, Sönke; Steffen , P; Bachmann, Kai Alexander; Steglich, Babett; Schrader, Jörg; Gagliani, Nicola; Schlüter, Hartmut; Güngör, Cenap; Izbicki, Jakob; Wagener, Christoph; Bockhorn, Maximilian.

In: EXP MOL MED, Vol. 50, No. 10, 133, 10.10.2018, p. 1-13.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Wolters-Eisfeld, G, Mercanoglu, B, Hofmann, BT, Wolpers, T, Schnabel, C, Harder, S, Steffen , P, Bachmann, KA, Steglich, B, Schrader, J, Gagliani, N, Schlüter, H, Güngör, C, Izbicki, J, Wagener, C & Bockhorn, M 2018, 'Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice', EXP MOL MED, vol. 50, no. 10, 133, pp. 1-13. https://doi.org/10.1038/s12276-018-0157-3, https://doi.org/10.1038/s12276-018-0157-3, https://doi.org/10.1038/s12276-018-0157-3

APA

Wolters-Eisfeld, G., Mercanoglu, B., Hofmann, B. T., Wolpers, T., Schnabel, C., Harder, S., Steffen , P., Bachmann, K. A., Steglich, B., Schrader, J., Gagliani, N., Schlüter, H., Güngör, C., Izbicki, J., Wagener, C., & Bockhorn, M. (2018). Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice. EXP MOL MED, 50(10), 1-13. [133]. https://doi.org/10.1038/s12276-018-0157-3, https://doi.org/10.1038/s12276-018-0157-3, https://doi.org/10.1038/s12276-018-0157-3

Vancouver

Wolters-Eisfeld G, Mercanoglu B, Hofmann BT, Wolpers T, Schnabel C, Harder S et al. Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice. EXP MOL MED. 2018 Oct 10;50(10):1-13. 133. https://doi.org/10.1038/s12276-018-0157-3, https://doi.org/10.1038/s12276-018-0157-3, https://doi.org/10.1038/s12276-018-0157-3

Bibtex

@article{75fbf9e83d624e80a5ebd73de5619f4e,
title = "Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice",
abstract = "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.",
keywords = "Animals, Cells, Cultured, Diabetes Mellitus, Type 2/etiology, Disease Models, Animal, Glycosylation, Insulin-Secreting Cells/metabolism, Male, Mice, Mice, Knockout, Molecular Chaperones/genetics, Pancreas, Exocrine/metabolism, Proteome, Proteomics/methods",
author = "Gerrit Wolters-Eisfeld and Baris Mercanoglu and Hofmann, {Bianca Thidahan} and Thomas Wolpers and Claudia Schnabel and S{\"o}nke Harder and P Steffen and Bachmann, {Kai Alexander} and Babett Steglich and J{\"o}rg Schrader and Nicola Gagliani and Hartmut Schl{\"u}ter and Cenap G{\"u}ng{\"o}r and Jakob Izbicki and Christoph Wagener and Maximilian Bockhorn",
year = "2018",
month = oct,
day = "10",
doi = "10.1038/s12276-018-0157-3",
language = "English",
volume = "50",
pages = "1--13",
journal = "EXP MOL MED",
issn = "1226-3613",
publisher = "Korean Society of Med. Biochemistry and Mol. Biology",
number = "10",

}

RIS

TY - JOUR

T1 - Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice

AU - Wolters-Eisfeld, Gerrit

AU - Mercanoglu, Baris

AU - Hofmann, Bianca Thidahan

AU - Wolpers, Thomas

AU - Schnabel, Claudia

AU - Harder, Sönke

AU - Steffen , P

AU - Bachmann, Kai Alexander

AU - Steglich, Babett

AU - Schrader, Jörg

AU - Gagliani, Nicola

AU - Schlüter, Hartmut

AU - Güngör, Cenap

AU - Izbicki, Jakob

AU - Wagener, Christoph

AU - Bockhorn, Maximilian

PY - 2018/10/10

Y1 - 2018/10/10

N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Diabetes Mellitus, Type 2/etiology

KW - Disease Models, Animal

KW - Glycosylation

KW - Insulin-Secreting Cells/metabolism

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Molecular Chaperones/genetics

KW - Pancreas, Exocrine/metabolism

KW - Proteome

KW - Proteomics/methods

UR - https://rdcu.be/8Wkn

U2 - 10.1038/s12276-018-0157-3

DO - 10.1038/s12276-018-0157-3

M3 - SCORING: Journal article

C2 - 30305605

VL - 50

SP - 1

EP - 13

JO - EXP MOL MED

JF - EXP MOL MED

SN - 1226-3613

IS - 10

M1 - 133

ER -