Journal
EMBO REPORTS
Volume 21, Issue 6, Pages -Publisher
WILEY
DOI: 10.15252/embr.201948885
Keywords
3D skin; differential glycoproteomics; polyomics; polypeptide GalNAc-transferase; tissue development
Categories
Funding
- European Commission [GlycoSkin H2020-ERC GAP-772735]
- Danish National Research Foundation [DNRF107]
- Friis Foundation
- Michelsen Foundation
- Danish Research Councils (Sapere Aude Research Leader grant)
- Novo Nordisk Foundation
- Danish Strategic Research Council
- Lundbeck Foundation [R219-2016-545]
- University of Copenhagen
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Post-translational modifications (PTMs) greatly expand the function and potential for regulation of protein activity, and O-glycosylation is among the most abundant and diverse PTMs. Initiation of O-GalNAc glycosylation is regulated by 20 distinct GalNAc-transferases (GalNAc-Ts), and deficiencies in individual GalNAc-Ts are associated with human disease, causing subtle but distinct phenotypes in model organisms. Here, we generate a set of isogenic keratinocyte cell lines lacking either of the three dominant and differentially expressed GalNAc-Ts. Through the ability of keratinocytes to form epithelia, we investigate the phenotypic consequences of the loss of individual GalNAc-Ts. Moreover, we probe the cellular responses through global transcriptomic, differential glycoproteomic, and differential phosphoproteomic analyses. We demonstrate that loss of individual GalNAc-T isoforms causes distinct epithelial phenotypes through their effect on specific biological pathways; GalNAc-T1 targets are associated with components of the endomembrane system, GalNAc-T2 targets with cell-ECM adhesion, and GalNAc-T3 targets with epithelial differentiation. Thus, GalNAc-T isoforms serve specific roles during human epithelial tissue formation.
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