PRMT5 is crucial to endometrial stromal cell differentiation by modulating the crosstalk between methylation and phosphorylation of Nur77

Various posttranslational modifications (PTMs) have been interpreted in endometrial stromal cell (EnSC) differentiation, but the potential role of PTMs crosstalk has not been identified. Here, we report that protein arginine methyltransferase 5 (PRMT5) is indispensable for human endometrial decidualization, serving as a key regulator of decidualization defect in recurrent implantation failure (RIF) patients. Uterine-selective Prmt5-KO mice exhibit defective embryo implantation due to impaired EnSC decidualization. Mechanistically, we find that PRMT5 catalyzes symmetric dimethylation of Nur77 at arginine 346 (R346), which is benefit to the nuclear localization and transcriptional activity of Nur77 in EnSC. Moreover, we discover that the accumulation of methylation of Nur77 at R346 can antagonize phosphorylation of Nur77 by AKT at serine 351 in the transition from proliferation to differentiation of EnSC. Whereas, the balance between methylation and phosphorylation of Nur77 is disturbed in the endometrium of RIF patients. We further explore the experimental treatments to rescue impaired decidualization in RIF by modulating the methylation-phosphorylation role on Nur77 transcriptional activity, further delineation of these molecular mechanisms of PRMT5/AKT/Nur77 complex will be interesting, challenging and beneficial for developing therapeutic targets for embryo implantation failure.