Journal Article

EHD1 impaired decidualization of endometrial stromal cells in recurrent implantation failure: role of SENP1 in modulating progesterone receptor signalling

Wu, Min, Yan, Guijun, Zhang, Hui, Jiang, Ruiwei, Wang, Xiaoying, Kong, Na, Liu, Yang, Zhu, Yinchun, Jiang, Yue, Kong, Liping, Kang, Yu, Zhen, Xin, Sun, Haixiang, Cao, Zhiwen, Zhou, Jidong

2024

Overview

Recurrent implantation failure (RIF) patients exhibit poor endometrial receptivity and abnormal decidualization with reduced effectiveness and exposure to progesterone, which is an intractable clinical problem. However, the associated molecular mechanisms remain elusive. We found that EH domain containing 1 (EHD1) expression was abnormally elevated in RIF and linked to aberrant endometrial decidualization. Here we show that EHD1 overexpressed in human endometrial stromal cells significantly inhibited progesterone receptor (PGR) transcriptional activity and the responsiveness to progesterone. No significant changes were observed in PGR mRNA levels, while a significant decrease in progesterone receptor B (PRB) protein level. Indeed, EHD1 binds to the PRB protein, with the K388 site crucial for this interaction. Overexpression of EHD1 promotes the SUMOylation and ubiquitination of PRB, leading to the degradation of the PRB protein. Supplementation with the de-SUMOylated protease SENP1 ameliorated EHD1–repressed PRB transcriptional activity. To establish a functional link between EHD1 and the PGR signalling pathway, sg-EHD1 were utilized to suppress EHD1 expression in HESCs from RIF patients. A significant increase in the expression of prolactin and insulin-like growth factor-binding protein 1 was detected by interfering with the EHD1. In conclusion, we demonstrated that abnormally high expression of EHD1 in endometrial stromal cells attenuated the activity of PRB associated with progesterone resistance in a subset of women with RIF. Summary Sentence EH homeodomain 1 (EHD1) modulates PRB expression by promoting the ubiquitinated degradation of PRB regulated by SENP1, indicating the function of EHD1 in PRB protein stability and transcriptional activity in human endometrial stromal cells of recurrent implantation failure. Graphical Abstract

• Publisher: Society for the Study of Reproduction,Oxford University Press
• Subject: Cysteine Endopeptidases / Decidua - metabolism / decidualization / domain / EHD1 / Endometrium / Endometrium - metabolism / Female / Humans / insulin-like growth factor binding proteins / Insulin-like growth factor-binding protein 1 / Molecular modelling / Progesterone / Progesterone - metabolism / Progesterone - pharmacology / progesterone receptor / progesterone receptors / Prolactin / protein content / proteinases / Proteins / Receptors, Progesterone - genetics / Receptors, Progesterone - metabolism / recurrent implantation failure (RIF) / reproduction / RESEARCH ARTICLE / SENP1 / Signal transduction / Stromal cells / Stromal Cells - metabolism / SUMO protein / sumoylation / transcription (genetics) / Ubiquitination / Vesicular Transport Proteins - metabolism