Ubiquitin‐specific protease 7 (USP7) is essential for endometrial stromal cell decidualization in mice

Abstract

Ubiquitin‐specific protease 7 (USP7), a member of the deubiquitinating (DUB) enzyme family, regulates protein stability and has a well‐characterized function in tumorigenesis. Given its critical role in growth and development, it was speculated to be involved in modulating processes in the female reproductive system but its exact role has not been elucidated. Decidualization is one of the key processes in pregnancy and aberrant decidualization is a cause of pregnancy failure. The uterine endometrium layer undergoes significant structural and functional changes during decidualization in preparation for and after embryo implantation. Here, we hypothesized that USP7 could be involved in mediating endometrial stromal cell (ESC) decidualization and set out to determine its function with a primary stromal cell culture. Using in situ hybridization and immunohistochemical techniques, we observed increased USP7 expression during uterine decidualization and found that it was predominantly localized to the decidual zone in the post‐implantation uterus. Since the ovarian hormones, progesterone (P4) and estrogen (E2), function in promoting stroma decidualization, we investigated their relationship with USP7 expression and found that they exert minimal influence. Moreover, increased USP7 expression observed during deciduoma development was found to be independent of blastocyst attachment. Using a specific USP7 inhibitor, HBX19818, we demonstrated an additional novel role for USP7 in endometrial stroma decidualization in mice during early pregnancy. Our findings could potentially be applied towards future research and development in female infertility.

TIP60 governs the auto‑ubiquitination of UHRF1 through USP7 dissociation from the UHRF1/USP7 complex

“…Ubiquitination is a post-translational modification which adds single or multiple ubiquitin molecules to proteins marking them for proteasomal degradation, cellular trafficking, autophagy, DNA repair, receptor internalization or regulation of enzymatic activity ( 81 , 82 ). USP7 is a deubiquitinating enzyme which protects many proteins from ubiquitination including p53, UHRF1, PTEN, MDM2 and Myc.…”

“…Its expression levels are high in a number of cancers. Dysregulation in ubiquitination/deubiquitination can play a critical role in several diseases, including cancer ( 81 ). USP7 interacts with UHRF1 and protects it from degradation ( 58 , 83 ) while during the M phase, UHRF1 is degraded as a result of its dissociation from USP7 ( 66 ).…”

TIP60 governs the auto-ubiquitination of UHRF1 through USP7 dissociation from the UHRF1/USP7 complex

“…Ubiquitination is a post-translational modi cation which adds single or multiple ubiquitin molecules to proteins marking them for proteasomal degradation, cellular tra cking, autophagy, DNA repair, receptor internalization or regulation of enzymatic activity [77,78]. USP7 is a deubiquitinating enzyme which protects many proteins from ubiquitination including p53, UHRF1, PTEN, MDM2 and Myc.…”

“…Its expression levels are high in many cancers. Dysregulation in ubiquitylation/deubiquitylation can play a critical role in several diseases including cancer [77]. USP7 interacts with UHRF1 and protects it from degradation [58,79] while during the M phase, UHRF1 is degraded as a result of its dissociation from USP7 [64].…”

USP25 Regulates the Proliferation and Apoptosis of Ovarian Granulosa Cells in Polycystic Ovary Syndrome by Modulating the PI3K/AKT Pathway via Deubiquitinating PTEN

“…Ubiquitination is a post-translational modification (PTM) process in which a highly conserved ubiquitin polypeptide is added to proteins, either as a single molecule or as a chain of ubiquitin molecules, to control their stability, activity, cellular localization, protein–protein interactions, and proteolysis by the 26S proteasome ( Hussain et al, 2009 ; Gallo and Dirks, 2016 ; Gao et al, 2019 ). The PTM of transcriptional coregulators appears to be a crucial mechanism for regulating fundamental biological functions, according to increasing data ( Lecona et al, 2016 ; Grumati and Dikic, 2018 ).…”