泛素连接酶
子宫内膜
孕酮受体
内分泌学
泛素
内科学
p38丝裂原活化蛋白激酶
生物
雌激素
雌激素受体
雌激素受体α
磷酸化
细胞生物学
化学
MAPK/ERK通路
医学
生物化学
癌症
乳腺癌
基因
作者
Yedong Tang,Jingtao Qiu,Zhenzhou Tang,Gaizhen Li,Mengqing Gu,Yan Wang,Haili Bao,Wenbo Deng,Zhongxian Lu,Kinya Otsu,Zhengchao Wang,Haibin Wang,Shuangbo Kong
标识
DOI:10.1073/pnas.2206000119
摘要
Estrogen and progesterone specify the establishment of uterine receptivity mainly through their respective nuclear receptors, ER and PR. PR is transcriptionally induced by estrogen-ER signaling in the endometrium, but how the protein homeostasis of PR in the endometrium is regulated remains elusive. Here, we demonstrated that the uterine-selective depletion of P38α derails normal uterine receptivity ascribed to the dramatic down-regulation of PR protein and disordered progesterone responsiveness in the uterine stromal compartment, leading to defective implantation and female infertility. Specifically, Ube3c, an HECT family E3 ubiquitin ligase, targets PR for polyubiquitination and thus proteasome degradation in the absence of P38α. Moreover, we discovered that P38α restrains the polyubiquitination activity of Ube3c toward PR by phosphorylating the Ube3c at serine741 . In summary, we provided genetic evidence for the regulation of PR protein stability in the endometrium by P38α and identified Ube3c, whose activity was modulated by P38α-mediated phosphorylation, as an E3 ubiquitin ligase for PR in the uterus.
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