COPS5 negatively regulates <i>goat</i> endometrial function via the ERN1 and mTOR‐autophagy pathways during early pregnancy

Yang, Diqi; Zhang, Beibei; Wang, Zongjie; Zhang, Linlin; Chen, Huatao; Zhou, Dong; Tang, Kai-Fu; Wang, Aihua; Lin, Peng; Jin, Yaping

doi:10.1002/jcp.28505

Cited by 8 publications

(8 citation statements)

References 55 publications

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“…Thus, it is possible that Cops5 regulates the autophagy of Mtch2 by deubiquitinating Mtch2. In addition, it has been shown that Cops5 regulates autophagy via the ERN1 and mTOR pathways in goat endometrial epithelial cells (38). Given that Cops5 interacts with the mitochondrial protein Mtch2, the possibility is raised that Cops5 regulates mitophagy or, even more specifically, the autophagy of Mtch2.…”

Section: Discussionmentioning

confidence: 99%

Cops5 safeguards genomic stability of embryonic stem cells through regulating cellular metabolism and DNA repair

Gao

Cui

Zhang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The highly conserved COP9 signalosome (CSN), composed of 8 subunits (Cops1 to Cops8), has been implicated in pluripotency maintenance of human embryonic stem cells (ESCs). Yet, the mechanism for the CSN to regulate pluripotency remains elusive. We previously showed that Cops2, independent of the CSN, is essential for the pluripotency maintenance of mouse ESCs. In this study, we set out to investigate how Cops5 and Cops8 regulate ESC differentiation and tried to establish Cops5 and Cops8 knockout (KO) ESC lines by CRISPR/Cas9. To our surprise, no Cops5 KO ESC clones were identified out of 127 clones, while three Cops8 KO ESC lines were established out of 70 clones. We then constructed an inducible Cops5 KO ESC line. Cops5 KO leads to decreased expression of the pluripotency marker Nanog, proliferation defect, G2/M cell-cycle arrest, and apoptosis of ESCs. Further analysis revealed dual roles of Cops5 in maintaining genomic stability of ESCs. On one hand, Cops5 suppresses the autophagic degradation of Mtch2 to direct cellular metabolism toward glycolysis and minimize reactive oxygen species (ROS) production, thereby reducing endogenous DNA damage. On the other hand, Cops5 is required for high DNA damage repair (DDR) activities in ESCs. Without Cops5, elevated ROS and reduced DDR activities lead to DNA damage accumulation in ESCs. Subsequently, p53 is activated to trigger G2/M arrest and apoptosis. Altogether, our studies reveal an essential role of Cops5 in maintaining genome integrity and self-renewal of ESCs by regulating cellular metabolism and DDR pathways.

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Section: Discussionmentioning

confidence: 99%

Cops5 safeguards genomic stability of embryonic stem cells through regulating cellular metabolism and DNA repair

Gao

Cui

Zhang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Figure 2 E shows that the reduction in PGR and ESR1 was found compared with the shN group, but there were no significant differences in IFNAR1 and IFNAR2 between the shN and shBCL2L15 groups. We also found a knockdown of BCL2L15 reduced the expression of HOXA10 , HOXA11, and LIF , which served as the key markers for endometrial receptivity [ 19 , 23 ] ( Figure 2 F).…”

Section: Resultsmentioning

confidence: 85%

“…Endometrial receptivity is a prerequisite to render the uterus suitable for embryo adhesion and to establish pregnancy in ruminants [18,19]. Although the molecular mechanism of regulating endometrial receptivity remains unclear, it is well-documented that altered gene expression in EECs during early pregnancy guarantees the success of embryo implantation [32].…”

Section: Discussionmentioning

confidence: 99%

“…We isolated mRNA and proteins from EECs to examine the BCL2L15 mRNA and protein levels in EECs under progesterone (P 4 ), estradiol (E 2 ), and IFN-τ treatments, which were adopted to mimic the in vivo intrauterine environment during the WOI [17][18][19]. Compared with the control (CON) group, the BCL2L15 mRNA levels significantly increased at 12 h. Next, we assessed the BCL2L15 expression in protein extracts prepared from EECs at 3, 6, and 12 h under P 4 , E 2 , and IFN-τ treatments.…”

Section: Hormone and Ifn-τ Treatment Triggered Bcl2l15mentioning

confidence: 99%

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BCL2L15 Depletion Inhibits Endometrial Receptivity via the STAT1 Signaling Pathway

Yang

et al. 2020

Genes

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In domestic ruminants, endometrial receptivity is critical for a successful pregnancy and economic efficiency. Although the endometrium undergoes major cellular changes during peri-implantation, the precise mechanisms regulating goat endometrial receptivity remain unknown. In this study, we investigated the functional roles and signal transduction of the B-cell lymphoma 2 (Bcl-2)-like protein 15 (BCL2L15) in the regulation of endometrial receptivity in vitro. Our results showed that BCL2L15 was up-regulated in goat endometrial epithelial cells (EECs) under progesterone (P4), estradiol (E2), and interferon-tau (IFN-τ) treatments. Our knockdown of BCL2L15 by specific shRNA that significantly hampered endometrial receptivity. In the absence of BCL2L15, the signal transducer and activator of transcription (STAT)1 and STAT3 pathway were activated. Additionally, pretreatment with the STAT1 inhibitor, fludarabine, restored the effect of silencing BCL2L15 on the endometrial receptivity, but not the STAT3 inhibitor Stattic. Overall, these results suggested that BCL2L15 is the key regulator of endometrial receptivity in goats, regulating the endometrial receptivity through the STAT1 pathway. Understanding the function of BCL2L15-STAT1 in endometrial receptivity is important to the exploration of new targets for the diagnosis and treatment of early pregnancy failure, and improving the success rates for artificial reproduction.

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“…Accumulating evidence indicates that autophagy shows a close relationship with the cell proliferation, angiogenesis, cell apoptosis, prostaglandin secretion and cell attachment of endometrial epithelial cells [ 27 , 28 , 29 ]. In particular, three recent studies have reported that autophagy appears to be the cruical pathway of endometrial regulation during early pregnancy in goat [ 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Essential Role of CRIM1 on Endometrial Receptivity in Goat

Yang

Zhang

et al. 2021

IJMS

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In domestic ruminants, endometrial receptivity is related to successful pregnancy and economic efficiency. Despite several molecules having been reported in the past regarding endometrial receptivity regulation, much regarding the mechanism of endometrial receptivity regulation remains unknown due to the complex nature of the trait. In this work, we demonstrated that the cysteine-rich transmembrane bone morphogenetic protein (BMP) regulator 1 (CRIM1) served as a novel regulator in the regulation of goat endometrial receptivity in vitro. Our results showed that hormones and IFN-τ increased the expression of CRIM1 in goat endometrial epithelial cells (EECs). Knockdown of CRIM1 via specific shRNA hindered cell proliferation, cell adhesion and prostaglandins (PGs) secretion and thus derailed normal endometrial receptivity. We further confirmed that receptivity defect phenotypes due to CRIM1 interference were restored by ATG7 overexpression in EECs while a loss of ATG7 further impaired receptivity phenotypes. Moreover, our results showed that changing the expression of ATG7 affected the reactive oxygen species (ROS) production. Moreover, mR-143-5p was shown to be a potential upstream factor of CRIM1-regulated endometrial receptivity in EECs. Overall, these results suggest that CRIM1, as the downstream target of miR-143-5p, has effects on ATG7-dependent autophagy, regulating cell proliferation, cell adhesion and PG secretion, and provides a new target for the diagnosis and treatment of early pregnancy failure and for improving the success rates of artificial reproduction.

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COPS5 negatively regulates goat endometrial function via the ERN1 and mTOR‐autophagy pathways during early pregnancy

Cited by 8 publications

References 55 publications

Cops5 safeguards genomic stability of embryonic stem cells through regulating cellular metabolism and DNA repair

Cops5 safeguards genomic stability of embryonic stem cells through regulating cellular metabolism and DNA repair

BCL2L15 Depletion Inhibits Endometrial Receptivity via the STAT1 Signaling Pathway

Essential Role of CRIM1 on Endometrial Receptivity in Goat

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