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

Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2206000119. doi: 10.1073/pnas.2206000119. Epub 2022 Aug 1.

Abstract

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.

Keywords: P38α; Ube3c; progesterone receptor; uterine receptivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Embryo Implantation* / physiology
  • Endometrium / metabolism
  • Female
  • Infertility, Female
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinase 14* / metabolism
  • Phosphorylation
  • Progesterone* / metabolism
  • Receptors, Progesterone / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • Uterus* / enzymology
  • Uterus* / metabolism

Substances

  • Receptors, Progesterone
  • Progesterone
  • Ubiquitin-Protein Ligases
  • Mitogen-Activated Protein Kinase 14