Protein N-glycosylation is a common post-translational modification that produces a complex array of branched glycan structures. The levels of branching, or antennarity, give rise to differential biological activities for single glycoproteins. However, the precise mechanism controlling the glycan branching and glycosylation network is unknown. Here, we constructed quantitative mathematical models of N-linked glycosylation that predicted new control points for glycan branching. Galactosyltransferase, which acts on N-acetylglucosamine residues, was unexpectedly found to control metabolic flux through the glycosylation pathway and the level of final antennarity of nascent protein produced in the Golgi network. To further investigate the biological consequences of glycan branching in nascent proteins, we glycoengineered a series of mammalian cells overexpressing human chorionic gonadotropin (hCG). We identified a mechanism in which galactosyltransferase 4 isoform regulated N-glycan branching on the nascent protein, subsequently controlling biological activity in an in vivo model of hCG activity. We found that galactosyltransferase 4 is a major control point for glycan branching decisions taken in the Golgi of the cell, which might ultimately control the biological activity of nascent glycoprotein.
Pregnancy-specific glycoproteins are secreted by immunoglobulin superfamily members encoded by multigene families in eutherian mammals with haemochorial placentation. They are expressed predominantly in placental trophoblast and exhibit immunomodulatory, anti-platelet, and pro-angiogenic functions. An inversion of Psg22 in the mouse locus is associated with relatively high Psg22 expression in the first half of the pregnancy. Bioinformatic analyses of 17 mouse strains indicated that Psg22 inversion arose at least 1.7 MYA. We used CRISPR-Cas9 mutagenesis to generate Psg22-null mutants, two of which were analysed in detail (Psg22 Δ10 and Psg22 Δ16). Both mutants contain frame-shifting deletions in exon 2, resulting in premature stop codons, and Psg22 mRNA was virtually undetectable. Both mutants are fertile and there was no distortion of Mendelian ratios in heterozygous crosses. Housing of pregnant females in a hypoxic (11% O 2) environment for 5 (E5-E10) or 10 (E5-E15) days did not induce differential growth or survival of Psg22 wildtype and null mutant genotypes. Our results indicate that Psg22 is dispensable for embryonic development and reproduction under laboratory conditions. As PSGs are secreted into maternal blood, future work will focus on whether Psg22 deficiency alters maternal physiology.
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