Gαq-PKD/PKCμ signal regulating the nuclear export of HDAC5 to induce the IκB expression and limit the NF-κB-mediated inflammatory response essential for early pregnancy

  1. Yufei Jiang
  2. Yan He
  3. Songting Liu
  4. Gaizhen Li
  5. Dunjin Chen
  6. Wenbo Deng
  7. Ping Li
  8. Ying Zhang
  9. Jinxiang Wu
  10. Jianing Li
  11. Longmei Wang
  12. Jiajing Lin
  13. Haibin Wang
  14. Shuangbo Kong
  15. Guixiu Shi

  • Curated by eLife

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    eLife assessment

    This study presents a valuable finding on the role and function of the Gaq axis on the inflammatory response during decidualization essential for early pregnancy. The evidence supporting the claims of the authors is solid, although some of the methodology and data interpretation require further clarification and justification. The work will be of interest to reproductive biologists and clinicians.

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Abstract

Decidualization, denoting the transformation of endometrial stromal cells into specialized decidual cells, is a prerequisite for normal embryo implantation and a successful pregnancy in human. Here, we demonstrated that knockout of Gαq lead to an aberrantly enhanced inflammatory state during decidualization. Furthermore, we showed that deficiency of Gαq resulted in over-activation of nuclear factor (NF)-κB signaling, due to the decreased expression of NFκBIA , which encode the IκB protein and is the negative regulator for NF-κB. Mechanistically, Gαq deficiency decreased the Protein kinase D (PKD, also called PKCμ) phosphorylation levels, leading to attenuated HDAC5 phosphorylation and thus its nuclear export. Aberrantly high level of nuclear HDAC5 retarded histone acetylation to inhibit the induced NFκBIA transcription during decidualization. Consistently, pharmacological activation of the PKD/PKCμ or inhibition of the HDAC5 restored the inflammatory state and proper decidual response. Finally, we disclosed that over-active inflammatory state in Gαq-deficient decidua deferred the blastocyst hatching and adhesion in vitro, and the decidual expression of Gαq was significantly lower in women with recurrent pregnancy loss compared with normal pregnancy. In brief, we showed here that Gαq as a key regulator of the inflammatory cytokine’s expression and decidual homeostasis in response to differentiation cues, which is required for successful implantation and early pregnancy.

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  1. Version published to 10.7554/elife.83083 on eLife
  2. eLife

    eLife assessment

    This study presents a valuable finding on the role and function of the Gaq axis on the inflammatory response during decidualization essential for early pregnancy. The evidence supporting the claims of the authors is solid, although some of the methodology and data interpretation require further clarification and justification. The work will be of interest to reproductive biologists and clinicians.

  3. eLife

    Reviewer #1 (Public Review):

    Decidualization, denoting the transformation of endometrial stromal cells into specialized decidual cells, is a prerequisite for normal embryo implantation and successful pregnancy in humans. Abnormal cytokine-associated inflammation during decidualization can alter the endometrium's receptivity to healthy embryo implantation. Jiang and colleagues present an important analysis of the role and function of the Gaq axis on the inflammatory response during decidualization essential for early pregnancy, and present preliminary data on its clinical relevance.

    The data narrative provides solid evidence of the mechanisms suggested by Jiang and colleagues. The study is highlighted both by the in vitro analysis and also by the study of human samples and subjects impacted by Recurrent Pregnancy Loss (RPL). Overall, the data seems to justify the conclusions taken, although some of the methodology and data interpretation require further clarification and justification.

  4. eLife

    Reviewer #2 (Public Review):

    This manuscript provided evidence that Gaq is a key regulator of the expression of inflammatory cytokines to maintain the proper progress of decidualization of human endometrial stromal cells for successful implantation and pregnancy. The major strength of the manuscript is the experimental design to answer sequential scientific questions regarding the function of Gaq during decidualization in the human endometrium using various molecular and pharmacologic tools. A weak point of this manuscript is that the author did not provide a reason to focus on HDAC5 among various downstream targets for the study of Gaq. In addition, if the authors make a knockout mouse of Gaq and characterize its phenotypes to support what they found in human stromal cells, the findings in this manuscript could become a piece of compelling evidence for the importance of Gaq during decidualization in the human endometrium for a successful pregnancy. This could be the next scientific topic for the authors to pursue this project.

  5. Version published to 10.1101/2022.10.17.512513v1 on bioRxiv