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
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 decidua...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2023-07-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/83083 |
| _version_ | 1797771149060341760 |
|---|---|
| author | Yufei Jiang Yan He Songting Liu Gaizhen Li Dunjin Chen Wenbo Deng Ping Li Ying Zhang Jinxiang Wu Jianing Li Longmei Wang Jiajing Lin Haibin Wang Shuangbo Kong Guixiu Shi |
| author_facet | Yufei Jiang Yan He Songting Liu Gaizhen Li Dunjin Chen Wenbo Deng Ping Li Ying Zhang Jinxiang Wu Jianing Li Longmei Wang Jiajing Lin Haibin Wang Shuangbo Kong Guixiu Shi |
| author_sort | Yufei Jiang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T21:33:21Z |
| format | Article |
| id | doaj.art-3b71c68374504af9a19850bf1d9cd595 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T21:33:21Z |
| publishDate | 2023-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3b71c68374504af9a19850bf1d9cd5952023-07-27T15:12:26ZengeLife Sciences Publications LtdeLife2050-084X2023-07-011210.7554/eLife.83083Gαq-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 pregnancyYufei Jiang0https://orcid.org/0000-0002-0048-1241Yan He1Songting Liu2Gaizhen Li3Dunjin Chen4Wenbo Deng5Ping Li6Ying Zhang7Jinxiang Wu8Jianing Li9Longmei Wang10Jiajing Lin11Haibin Wang12https://orcid.org/0000-0002-9865-324XShuangbo Kong13https://orcid.org/0000-0002-7513-4041Guixiu Shi14Xiamen Key Laboratory of Reproduction and Genetics, Department of Reproductive Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, ChinaXiamen Key Library of Rheumatology and Clinical Immunology, Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Pathology, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaXiamen Key Laboratory of Reproduction and Genetics, Department of Reproductive Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaXiamen Key Laboratory of Reproduction and Genetics, Department of Reproductive Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, ChinaDepartment of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaFujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaXiamen Key Library of Rheumatology and Clinical Immunology, Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, ChinaDecidualization, 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.https://elifesciences.org/articles/83083decidualizationearly pregnancyGαq-PKD/PKCμHDAC5inflammatory cytokine |
| spellingShingle | Yufei Jiang Yan He Songting Liu Gaizhen Li Dunjin Chen Wenbo Deng Ping Li Ying Zhang Jinxiang Wu Jianing Li Longmei Wang Jiajing Lin Haibin Wang Shuangbo Kong Guixiu Shi 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 eLife decidualization early pregnancy Gαq-PKD/PKCμ HDAC5 inflammatory cytokine |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | decidualization early pregnancy Gαq-PKD/PKCμ HDAC5 inflammatory cytokine |
| url | https://elifesciences.org/articles/83083 |
| work_keys_str_mv | AT yufeijiang gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT yanhe gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT songtingliu gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT gaizhenli gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT dunjinchen gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT wenbodeng gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT pingli gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT yingzhang gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT jinxiangwu gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT jianingli gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT longmeiwang gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT jiajinglin gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT haibinwang gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT shuangbokong gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy AT guixiushi gaqpkdpkcmsignalregulatingthenuclearexportofhdac5toinducetheikbexpressionandlimitthenfkbmediatedinflammatoryresponseessentialforearlypregnancy |