O-GlcNAc Modification During Pregnancy: Focus on Placental Environment

Abstract

Successful placentation is a key event for fetal development, which commences following embryo implantation into the uterine wall, eliciting decidualization, placentation, and remodeling of blood vessels to provide physiological exchange between embryo-fetus and mother. Several signaling pathways are recruited to modulate such important processes and specific proteins that regulate placental function are a target for the glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc), or O-GlcNAcylation. This is a reversible post-translational modification on nuclear and cytoplasmic proteins, mainly controlled by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAcylation has been implicated as a modulator of proteins, both in physiological and pathological conditions and, more recently, O-GlcNAc has also been shown to be an important modulator in placental tissue. In this mini-review, the interplay between O-GlcNAcylation of proteins and placental function will be addressed, discussing the possible implications of this post-translational modification through placental development and pregnancy.

Keywords: O-GlcNAc; placental dysfunction; placentation; post-translational modification; pregnancy.

FIGURE 1

Hexosamine biosynthetic pathway and O-glycosylation with O-linked β-N-acetylglucosamine during pregnancy. (Pink rectangle) Around 3–5% of intracellular glucose is converted through the HBP to substrate for enzymes involved in the synthesis of UDP-GlcNAc, consequently leading to protein modification through O-GlcNAc. OGT catalyzes the addition of O-GlcNAc to proteins, whereas OGA removes O-GlcNAc from proteins. (Bigger figure) Under physiological conditions, O-GlcNAc modifications to intracellular proteins are essential for embryogenesis, promoting the function and viability of various cell types. This process may be disrupted under specific conditions, including hyperglycemia or OGA disruption, where an increase in O-GlcNAc is observed, with a consequent reduction in cell proliferation, impaired blastocyst formation and decreased embryo viability. Abbreviations: HBP, Hexosamine biosynthetic pathway; O-GlcNAc, glycosylation with O-linked β-N-acetylglucosamine; OGA, β-N-acetylglucosaminidase; OGT, O-GlcNAc transferase.

FIGURE 2

Metabolic maternal stress and O-GlcNAc. O-GlcNAcylation appears to act as a stress sensor since it exerts its fundamental effects in response to stress. OGT has also been identified as a placental biomarker of cellular stress. During metabolic maternal stress and growth restriction, both OGT and O-GlcNAcylation were significantly lower. Placentas of female mice offspring had higher basal OGT expression compared to placentas of male offspring. However, following exposure to corticosterone, OGT expression raised in male placentas and remained the same in female placentas, simultaneously with increased global O-GlcNAcylation in female placentas, which was unmodified in male placentas. Abbreviations: O-GlcNAc, glycosylation with O-linked β-N-acetylglucosamine; OGA, β-N-acetylglucosaminidase; OGT, O-GlcNAc transferase.