Glycosyltransferase POMGNT1 deficiency strengthens N-cadherin-mediated cell-cell adhesion

• Verfasst von: Noor, Sina Ibne [VerfasserIn]
• Verfasst von: Hoffmann, Marcus [VerfasserIn]
• Verfasst von: Rinis, Natalia [VerfasserIn]
• Verfasst von: Bartels, Markus F. [VerfasserIn]
• Verfasst von: Winterhalter, Patrick R. [VerfasserIn]
• Verfasst von: Hölscher, Christina D. [VerfasserIn]
• Verfasst von: Hennig, Rene [VerfasserIn]
• Verfasst von: Himmelreich, Nastassja [VerfasserIn]
• Verfasst von: Thiel, Christian [VerfasserIn]
• Verfasst von: Ruppert, Thomas [VerfasserIn]
• Verfasst von: Rapp, Erdmann [VerfasserIn]
• Verfasst von: Strahl, Sabine [VerfasserIn]
• Titel: Glycosyltransferase POMGNT1 deficiency strengthens N-cadherin-mediated cell-cell adhesion
• Verf.angabe: Sina Ibne Noor, Marcus Hoffmann, Natalie Rinis, Markus F. Bartels, Patrick R. Winterhalter, Christina Hoelscher, Rene Hennig, Nastassja Himmelreich, Christian Thiel, Thomas Ruppert, Erdmann Rapp, and Sabine Strahl
• E-Jahr: 2021
• Jahr: February 18, 2021
• Umfang: 19 S.
• Fussnoten: Gesehen am 18.11.2021
• Titel Quelle: Enthalten in: The journal of biological chemistry
• Ort Quelle: Bethesda, Md. : ASBMB Publications, 1905
• Jahr Quelle: 2021
• Band/Heft Quelle: 296(2021), Artikel-ID 100433, Seite 1-19
• ISSN Quelle: 1083-351X
• DOI: doi:10.1016/j.jbc.2021.100433
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: basement-membrane
• Sach-SW: contributes
• Sach-SW: dystroglycan
• Sach-SW: epithelial-mesenchymal transition
• Sach-SW: expression
• Sach-SW: glycosylation pathway
• Sach-SW: laminin
• Sach-SW: migration
• Sach-SW: muscle
• Sach-SW: protein o-mannosylation
• K10plus-PPN: 1777961688

Abstract

Defects in protein O-mannosylation lead to severe congenital muscular dystrophies collectively known as alpha-dystroglycanopathy. A hallmark of these diseases is the loss of the O-mannose-bound matriglycan on alpha-dystroglycan, which reduces cell adhesion to the extracellular matrix. Mutations in protein O-mannose beta 1,2-N-acetylglucosaminyltransferase 1 (POMGNT1), which is crucial for the elongation of O-mannosyl glycans, have mainly been associated with muscle-eye-brain (MEB) disease. In addition to defects in cell-extracellular matrix adhesion, aberrant cell-cell adhesion has occasionally been observed in response to defects in POMGNT1. However, specific molecular consequences of POMGNT1 deficiency on cell-cell adhesion are largely unknown. We used POMGNT1 knockout HEK293T cells and fibroblasts from an MEB patient to gain deeper insight into the molecular changes in POMGNT1 deficiency. Biochemical and molecular biological techniques combined with proteomics, glycoproteomics, and glycomics revealed that a lack of POMGNT1 activity strengthens cell-cell adhesion. We demonstrate that the altered intrinsic adhesion properties are due to an increased abundance of N-cadherin (N-Cdh). In addition, site-specific changes in the N-glycan structures in the extracellular domain of N-Cdh were detected, which positively impact on homotypic interactions. Moreover, in POMGNT1-deficient cells, ERK1/2 and p38 signaling pathways are activated and transcriptional changes that are comparable with the epithelial-mesenchymal transition (EMT) are triggered, defining a possible molecular mechanism underlying the observed phenotype. Our study indicates that changes in cadherin-mediated cell-cell adhesion and other EMT-related processes may contribute to the complex clinical symptoms of MEB or alpha-dystroglycanopathy in general and suggests that the impact of changes in O-mannosylation on N-glycosylation has been underestimated.