TAZ as a novel regulator of oxidative damage in decidualization via Nrf2/ARE/Foxo1 pathway

• Published in: Experimental & molecular medicine Vol. 53; no. 9; pp. 1307 - 1318
• Main Authors: Yu, Hai-Fan, Zheng, Lian-Wen, Yang, Zhan-Qing, Wang, Yu-Si, Wang, Ting-Ting, Yue, Zhan-Peng, Guo, Bin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2021; Springer Nature B.V; 생화학분자생물학회
• Subjects: 13/2; 13/31; 13/51; 13/89; 14/19; 42/44; 631/136/2091; 631/443/494; 64/60; 82/80; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antioxidant Response Elements; Antioxidants; Antioxidants - metabolism; Apoptosis; Bax protein; Biomedical and Life Sciences; Biomedicine; Cell cycle; Cell Differentiation; Cell growth; Cell proliferation; Connective tissues; Copy number; Cyclin-dependent kinase 4; Decidua; Decidua - physiology; Detoxification; Electron transport; Embryogenesis; Female; Fertilization; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Gene Expression Regulation; Infertility; Medical Biochemistry; Membrane potential; Mice; Mitochondria - metabolism; Molecular Medicine; Mucosa; NF-E2-Related Factor 2 - metabolism; Ovulation; Oxidation-Reduction; Oxidative stress; Oxidative Stress - genetics; Phase transitions; Pregnancy; Proteins; Reactive Oxygen Species - metabolism; Recovery of function; RNA Interference; Rot; Signal Transduction; Spermatogenesis; Stem Cells; Stromal Cells - metabolism; Transcription; Uterus; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-021-00655-2

TAZ, as a crucial effector of Hippo pathway, is required for spermatogenesis and fertilization, but little is known regarding its physiological function in uterine decidualization. In this study, we showed that TAZ was localized in the decidua, where it promoted stromal cell proliferation followed by accelerated G1/S phase transition via Ccnd3 and Cdk4 and induced the expression or activity of stromal differentiation markers Prl8a2, Prl3c1 and ALP, indicating the importance of TAZ in decidualization. Knockdown of TAZ impeded HB-EGF induction of stromal cell proliferation and differentiation. Under oxidative stress, TAZ protected stromal differentiation against oxidative damage by reducing intracellular ROS and enhancing cellular antioxidant capacity dependent on the Nrf2/ARE/Foxo1 pathway. TAZ strengthened the transcriptional activity of Nrf2 which directly bound to the antioxidant response element (ARE) of Foxo1 promoter region. Additionally, silencing TAZ caused accumulation of intracellular ROS through heightening NOX activity whose blockade by APO reversed the disruption in stromal differentiation. Further analysis revealed that TAZ might restore mitochondrial function, as indicated by the increase in ATP level, mtDNA copy number and mitochondrial membrane potential with the reduction in mitochondrial superoxide. Additionally, TAZ modulated the activities of mitochondrial respiratory chain complexes I and III whose suppression by ROT and AA resulted in the inability of TAZ to defend against oxidative damage to stromal differentiation. Moreover, TAZ prevented stromal cell apoptosis by upregulating Bcl2 expression and inhibiting Casp3 activity and Bax expression. In summary, TAZ might mediate HB-EGF function in uterine decidualization through Ccnd3 and ameliorate oxidative damage to stromal cell differentiation via Nrf2/ARE/Foxo1 pathway. Reproduction: Protective protein readies uterus for pregnancy A protein known to regulate cell proliferation plays a key role in preparing a woman’s uterus for pregnancy, a finding that could inform future treatments for female infertility. A team led by Zhan-Peng Yue and Bin Guo from Jilin University, Changchun, China, examined the role of a co-activator protein called TAZ in decidualization, the process in which the uterine lining changes hormonally and biochemically following ovulation. The researchers showed that TAZ levels build up in the mucosal lining of the uterus, where the protein works with various regulators of the cell cycle to promote the proliferation of connective tissue cells known as stromal cells, which support early embryonic development. The researchers demonstrated that in the face of oxidative stress TAZ helps orchestrate molecular detoxification mechanisms that protect these stromal cells from damage.