GalNT2-mediated O-glycosylation affects pancreas development and function in mice

Abstract GALNT2, also known as polypeptide N-acetylgalactosaminyltransferase 2, is an enzyme that catalyzes the initial step of O-linked glycosylation, a crucial posttranslational modification that affects protein folding, stability, and function. Alterations in GALNT2 activity have been implicated in various diseases, such as cancer, metabolic disorders, and cardiovascular diseases, highlighting its importance in maintaining normal physiological functions. To investigate the impact of GalNT2 overexpression in vivo for the first time, we generated a conditional transgenic mouse line in which GalNT2 was expressed specifically in the pancreas. Heterozygous overexpression leads to a loss of acinar mass and pancreatic steatosis, whereas homozygous overexpression causes complete pancreatic loss and results in a lethal phenotype. Using a reporter gene mouse line, we demonstrated that adipocytes originate through transdifferentiation from pancreatic cells. GalNT2 overexpression results in additional O-glycosylation sites, which we analyzed through PNA lectin enrichment and mass spectrometric proteome analysis.