College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, 712100, China.
College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture and Rural Affairs, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Theriogenology. 2023 May;202:110-118. doi: 10.1016/j.theriogenology.2023.03.011. Epub 2023 Mar 11.
Interferon-tau (IFNT), a pregnancy recognition signal in ruminants, promotes the establishment of endometrial receptivity by inducing the expression of interferon-stimulated genes (ISGs) via the Janus kinase/signal transducer and activator of transcription (JAK/STATs) signaling pathway. However, the precise mechanisms remain largely unknown. Ubiquitin-specific protease 18 (USP18) acts specifically on the ISGylation modification system to exert deubiquitination and participates in the regulation of the type I IFN signaling pathway. The purpose of this study was to determine the role and mechanism of USP18 on endometrial receptivity in goat. USP18 was mainly localized in the uterine luminal and glandular epithelium, and its expression levels were significantly increased from days 5-18 of early pregnancy. Progesterone (P), estradiol (E), and IFNT significantly stimulated USP18 expression in goat endometrial epithelial cells (gEECs) cultured in vitro. Meanwhile, the markers of endometrial receptivity HOXA11, ITGB1, ITGB3, and ITGB5 were significantly upregulated after USP18 overexpression in gEECs. However, USP18 interference significantly inhibited the expression of HOXA10, ITGB1, ITGB3, and ITGB5 in gEECs. In addition, both the phosphorylation levels of STAT1 and the expression of ISGylation-modified proteins were significantly increased after USP18 silencing in gEECs. Furthermore, pretreatment with the STAT1 inhibitor Fludara markedly restored the effect of USP18 interference in gEECs. In summary, USP18 may play an important role in promoting goat endometrial receptivity by regulating the JAK/STAT1 pathway and ISGylation.
干扰素 tau（IFNT）是反刍动物妊娠识别信号，通过 Janus 激酶/信号转导和转录激活因子（JAK/STAT）信号通路诱导干扰素刺激基因（ISGs）的表达，促进子宫内膜容受性的建立。然而，其确切机制在很大程度上仍不清楚。泛素特异性蛋白酶 18（USP18）特异性作用于 ISG 化修饰系统，发挥去泛素化作用，并参与 I 型 IFN 信号通路的调节。本研究旨在确定 USP18 在山羊子宫内膜容受性中的作用和机制。USP18 主要定位于子宫腔和腺上皮，其表达水平从妊娠早期第 5-18 天显著增加。孕酮（P）、雌二醇（E）和 IFNT 显著刺激体外培养的山羊子宫内膜上皮细胞（gEEC）中 USP18 的表达。同时，USP18 过表达后，gEEC 中子宫内膜容受性标志物 HOXA11、ITGB1、ITGB3 和 ITGB5 的表达明显上调。然而，USP18 干扰明显抑制 gEECs 中 HOXA10、ITGB1、ITGB3 和 ITGB5 的表达。此外，USP18 沉默后 gEECs 中 STAT1 的磷酸化水平和 ISG 化修饰蛋白的表达明显增加。此外，STAT1 抑制剂 Fludara 的预处理显著恢复了 USP18 干扰在 gEECs 中的作用。总之，USP18 可能通过调节 JAK/STAT1 通路和 ISG 化来在促进山羊子宫内膜容受性方面发挥重要作用。
