Embryo implantation is a key step in successful pregnancy in mammals. More than 40% of the embryo loss is caused by embryo implantation failure, and the field of animal reproduction is focused on improving the rate of embryo implantation [1,2]. Embryo implantation includes three stages: localization, adhesion, and implantation [3,4]. Estrogen (E2), progesterone (P4) and pregnancy recognition signal interferon-tau (IFNT) induce together significant structural and functional changes in the endometrium to enable the establishment of endometrial receptivity and the subsequent successful embryo adhesion [5]. A series of complex signaling pathways, such as Janus kinase/signal transducer and activator of transcription (JAK/STATs), mammalian target of rapamycin (mTOR), and Wnt, are involved in the regulation of endometrial receptivity [[6], [7], [8], [9], [10]]. The JAK/STATs pathway plays an important role in reproductive processes. For example, the JAK/STAT3 pathway is activated during the implantation phase in mice and causes embryonic adhesion, trophoblast cell proliferation, invasion, etc. [6]. In ruminants, IFNT activates the JAK/STAT 1/2 pathway and induces the expression of a variety of interferon-stimulated genes (ISGs) that regulate pregnancy recognition processes [11,12]. Despite the continuous discovery of new regulators, further research on the mechanism underlying the formation of endometrial receptivity is required.

In general, functional changes in cells involve rapid changes in gene expression and protein posttranslational modifications (PTMs). Studies have shown that ubiquitination is involved in these processes [[13], [14]]. The binding of ISG15 to substrate proteins, a ubiquitin-like modifier, is known as ISGylation. However, ISGylation can be reversed by ubiquitin-specific protease 18 (USP18). USP18, a member of the ubiquitin-specific peptidase (USP) family, has been shown to contain interferon-stimulated response elements (ISREs) in its promoter region and is strongly induced by type I IFNs in multiple species [[15], [16], [17]]. USP18 is strongly expressed in the endometrium on day 18 of pregnancy, is significantly upregulated by IFNT in maternal peripheral blood leukocytes, and has been identified as a marker for early pregnancy diagnosis in dairy cows [18,19]. Although USP18 participates in the process of early pregnancy, its role and mechanism are still unclear. It can strip ISG15 from its target protein (deISGylation), which plays an important role in regulating type I IFN signaling in innate immunity [[20], [21], [22]]. However, additional evidence has recently shown that USP18 negatively regulates IFN signaling, mainly by competing with JAK1 for binding to interferon receptors (IFNARs) and inhibiting IFN-induced activation of the JAK/STAT signaling pathway [23]. In this study, we investigated the localization and expression of USP18 in goat endometrium during early pregnancy, as well as the effects of USP18 on endometrial receptivity in the cultured goat endometrial epithelial cells (gEECs).