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

• Published in: eLife Vol. 12
• Main Authors: Jiang, Yufei, He, Yan, Liu, Songting, Li, Gaizhen, Chen, Dunjin, Deng, Wenbo, Li, Ping, Zhang, Ying, Wu, Jinxiang, Li, Jianing, Wang, Longmei, Lin, Jiajing, Wang, Haibin, Kong, Shuangbo, Shi, Guixiu
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 27.07.2023; eLife Sciences Publications, Ltd
• Subjects: Acetylation; Active Transport, Cell Nucleus; Cell Biology; Cells; Cytokines; Decidua; Decidua - metabolism; decidualization; early pregnancy; Endometrium; Female; Genes; Genomes; GTP-Binding Proteins - metabolism; Gαq-PKD/PKCμ; Hatching; HDAC5; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones; Homeostasis; Humans; Implantation; Inflammation; inflammatory cytokine; Insulin-like growth factors; Kinases; Localization; Menstruation; NF-kappa B - metabolism; NF-κB protein; Nuclear transport; Phosphorylation; Pregnancy; Pregnancy complications; Protein deficiency; Protein kinase C; Protein Kinase C - metabolism; Proteins; Stromal cells; Stromal Cells - metabolism; Transcription factors; HDAC5; inflammatory cytokine; cell biology; Gαq-PKD/PKCμ; early pregnancy; none; decidualization
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.83083

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 , 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 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.