O-glycan initiation directs distinct biological pathways and controls epithelial differentiation
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O-glycan initiation directs distinct biological pathways and controls epithelial differentiation. / Bagdonaite, Ieva; Pallesen, Emil M. H.; Ye, Zilu; Vakhrushev, Sergey Y.; Marinova, Irina N.; Nielsen, Mathias I.; Kramer, Signe H.; Pedersen, Stine F.; Joshi, Hiren J.; Bennett, Eric P.; Dabelsteen, Sally; Wandall, Hans H.
In: EMBO Reports, Vol. 21, No. 6, e48885, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - O-glycan initiation directs distinct biological pathways and controls epithelial differentiation
AU - Bagdonaite, Ieva
AU - Pallesen, Emil M. H.
AU - Ye, Zilu
AU - Vakhrushev, Sergey Y.
AU - Marinova, Irina N.
AU - Nielsen, Mathias I.
AU - Kramer, Signe H.
AU - Pedersen, Stine F.
AU - Joshi, Hiren J.
AU - Bennett, Eric P.
AU - Dabelsteen, Sally
AU - Wandall, Hans H.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - 3D skin
KW - differential glycoproteomics
KW - polyomics
KW - polypeptide GalNAc-transferase
KW - tissue development
U2 - 10.15252/embr.201948885
DO - 10.15252/embr.201948885
M3 - Journal article
C2 - 32329196
AN - SCOPUS:85084092153
VL - 21
JO - E M B O Reports
JF - E M B O Reports
SN - 1469-221X
IS - 6
M1 - e48885
ER -
ID: 242296335