poFUT1 promotes endometrial decidualization by enhancing the O-fucosylation of Notch1

Abstract

Background Endometrial stromal cell decidualization is critical for embryo implantation. Dysfunctional decidualization leads to implantation failure, miscarriage and even pregnancy associated disorders in subsequent pregnancy trimesters. Protein glycosylation is involved in many physiological and pathological processes. Protein O-fucosyltransferase 1 (poFUT1) is the key enzyme for the O-fucosylation of proteins. However, the role and mechanism of poFUT1 in human endometrial stromal cell decidualization remain elusive. Methods We employed immunohistochemistry to detect the level of poFUT1 in the uterine endometrium from those of the proliferative phase, secretory phase, early pregnancy women and miscarriage patients. Using human endometrial stromal cells (hESCs) and a mouse model, the underlying mechanisms of poFUT1 in decidualization was investigated. Findings The level of poFUT1 was increased in the stromal cells of the secretory phase relative to those in the proliferative phase of the menstrual cycle, and decreased in the stromal cells of miscarriage patients compared to women with healthy early pregnancies. Furthermore, we found that poFUT1 promoted hESCs decidualization. The results also demonstrated that poFUT1 increased O-fucosylation on Notch1 in hESCs, which activated Notch1 signaling pathway. Activated Notch1 (NICD), as a specific trans-factor of PRL and IGFBP1 promoters, enhanced PRL and IGFBP1 transcriptional activity, thus inducing hESCs decidualization. Interpretation Level of poFUT1 is lower in the uterine endometrium from miscarriage patients than early pregnancy women. poFUT1 is critical in endometrial decidualization by controlling the O-fucosylation on Notch1. Our findings provide a new mechanism perspective on poFUT1 in uterine decidualization that may be a useful diagnostic and therapeutic target for miscarriage. Fund National Natural Science Foundation of China (31770857, 31670810 and 31870794). Liaoning Provincial Program for Top Discipline of Basic Medical Sciences.

Role of the early secretory pathway in SARS-CoV-2 infection

“…CoV-2 protein orf8 might support O-glycosylation by binding POGLUT2, POGLUT3, two O-glucosyltransferases, and POFUT1, an O-fucosyltransferase (Table 1). These enzymes have been shown to be pivotal for the proper glycosylation and presentation on the plasma membrane of the NOTCH1 receptor (Takeuchi et al, 2018;Yang et al, 2019;Okamura and Saga, 2008), confirming once more the importance of glycan processing in the maturation and transport of CoV-2 S and other proteins.…”

EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure

“…Decidualization is the differentiation of elongated, fibroblast-like mesenchymal cells into rounded, epithelioid-like cells under stimulation by progestogen and cyclic adenosine monophosphate (c-AMP) [6,7]. The morphological differentiation and hypermetabolic state of human endometrial stromal cells (HESCs) make them ready for subsequent embryo implantation [8], [9], [10]. However, few studies have investigated the molecular mechanisms underlying impaired decidualization during RIF.…”

Mouse model of menstruation: An indispensable tool to investigate the mechanisms of menstruation and gynaecological diseases (Review)

“…The poFuT1 expression was revealed to increase during the proliferation phase of the menstrual cycle; however, poFuT1 expression was reported to decrease in the endometrium during miscarriage. These results indicated that poFuT1 serves a key role in endometrial decidualisation, and may be therapeutically targeted to prevent spontaneous abortion (72).…”