P38α MAPK is a gatekeeper of uterine progesterone responsiveness at peri-implantation via Ube3c-mediated PGR degradation

• DOI: 10.1073/pnas.2206000119
• Publication Date: 2022-08-01T19:22:29Z
• Authors: Yedong Tang; Jingtao Qiu; Zhenzhou Tang; Gaizhen Li; Mengqing Gu; Yang Wang; Haili Bao; Wenbo Deng; Zhongxian Lu; Kinya Otsu; Zhengchao Wang; Haibin Wang; Shuangbo Kong
• Keywords: Progesterone receptor; Estrogen receptor alpha

Estrogen and progesterone specify the establishment of uterine receptivity mainly through their respective nuclear receptors, ER PR. PR is transcriptionally induced by estrogen-ER signaling in endometrium, but how protein homeostasis endometrium regulated remains elusive. Here, we demonstrated that uterine-selective depletion P38α derails normal ascribed to dramatic down-regulation disordered responsiveness stromal compartment, leading defective implantation female infertility. Specifically, Ube3c, an HECT family E3 ubiquitin ligase, targets for polyubiquitination thus proteasome degradation absence P38α. Moreover, discovered restrains activity Ube3c toward phosphorylating at serine741 . In summary, provided genetic evidence regulation stability identified whose was modulated P38α-mediated phosphorylation, as ligase uterus.