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MANF Promotes Unexplained Recurrent Miscarriages by Interacting with NPM1 and Downregulating Trophoblast Cell

Yuan Fang1,2,3,4, Junhui Zhang1,2,3,4, Damin Zhu1,3,4

  • 1Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, Anhui, China.

International Journal of Biological Sciences
|January 2, 2024
PubMed

Insights

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is elevated in unexplained recurrent miscarriages (URMs). MANF triggers miscarriage by degrading nucleophosmin 1 (NPM1), activating p53, and inhibiting trophoblast function.

Area of Science:

  • Reproductive Biology
  • Cell Biology
  • Immunology

Background:

  • Unexplained recurrent miscarriage (URM) is linked to trophoblast defects.
  • Mesencephalic astrocyte-derived neurotrophic factor (MANF) impacts cell migration and invasion.
  • The role of MANF in pregnancy disorders is not well understood.

Purpose of the Study:

  • To investigate the role of MANF in unexplained recurrent miscarriage (URM).
  • To elucidate the molecular mechanism by which MANF affects trophoblast function in URM.

Main Methods:

  • Quantification of MANF levels in URM patients' blood and tissues.
  • Analysis of MANF-nucleophosmin 1 (NPM1) interaction in trophoblasts.
  • Assessment of p53 signaling pathway activation.
  • In vivo studies using a URM mouse model.

Main Results:

  • MANF levels were higher in URM patients compared to controls.
  • MANF interacts with NPM1 in URM trophoblasts, promoting NPM1 ubiquitination and degradation.
  • This interaction upregulates the p53 pathway, inhibiting trophoblast proliferation, migration, and invasion.
  • MANF downregulation reduced fetal resorption in mice, while NPM1 downregulation increased abortion rates.

Conclusions:

  • MANF contributes to miscarriage in URM by downregulating NPM1 and activating p53.
  • The MANF-NPM1 interaction is a key mechanism in URM pathogenesis.
  • Targeting MANF or the MANF-NPM1 interaction may offer therapeutic strategies for URM.
Keywords:
MANFNPM1p53trophoblast cellsunexplained recurrent miscarriage

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