Function of COP9 Signalosome in Regulation of Mouse Oocytes Meiosis by Regulating MPF Activity and Securing Degradation

Kim, Eunju; Yoon, Se-Jin; Kim, Eun Young; Kim, Yunna; Lee, Hyun-Seo; Kim, Kyeoung‐Hwa; Lee, Kyung‐Ah

doi:10.1371/journal.pone.0025870

Cited by 11 publications

(9 citation statements)

References 54 publications

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“…Another study showed that the downregulation of the CSN led to the reduction of microtubule end-binding protein 1 (EB1) which is a regulator of microtubule dynamics (Peth et al, 2007 ). CSN3 or CSN5 knockdown caused disrupted meiotic spindle and misarranged chromosomes that result in failure to complete meiosis (Kim et al, 2011 ). Tubulin tyrosine ligase like-1 (TTLL1) belongs to the family of TTLL enzymes that catalyze the post-translational modifications of tubulin in order to modulate microtubule dynamics and function (Pathak et al, 2011 ).…”

Section: Resultsmentioning

confidence: 99%

Murine Myocardial Transcriptome Analysis Reveals a Critical Role of COPS8 in the Gene Expression of Cullin-RING Ligase Substrate Receptors and Redox and Vesicle Trafficking Pathways

et al. 2017

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Background: The COP9 signalosome (CSN) consisting of 8 unique protein subunits (COPS1 through COPS8) serves as the cullin deneddylase, regulating the catalytic dynamics of cullin RING ligases (CRLs), the largest family of ubiquitin ligases Background: The COP9 signalosome (CSN) consisting of 8 unique protein subunits (COPS1 through COPS8) serves as the cullin deneddylase, regulating the catalytic dynamics of cullin RING ligases (CRLs), the largest family of ubiquitin ligases. Supported primarily by the decrease of substrate receptor (SR) proteins of CRLs in cells deficient of a CSN subunit, CSN-mediated cullin deneddylation is believed to prevent autoubiquitination and self-destruction of the SR in active CRLs. However, it is unclear whether the decrease in SRs is solely due to protein destabilization. Moreover, our prior studies have demonstrated that cardiac specific knockout of Cops8 (Cops8-CKO) impairs autophagosome maturation and causes massive necrosis in cardiomyocytes but the underlying mechanism remains poorly understood. Given that Cops8 is nucleus-enriched and a prior report showed its binding to the promoter of several genes and association of its ablation with decreased mRNA levels of these genes, we sought to determine the dynamic changes of myocardial transcriptome in mice with perinatal Cops8-CKO and to explore their functional implications.Methods and Results: Myocardial transcriptomes of Cops8flox/flox, Cops8flox/+::Myh6-Cre, and Cops8flox/flox::Myh6-Cre littermate mice at postnatal 2 and 3 weeks were analyzed. The data were imported into an in-house analysis pipeline using Bioconductor for quantile normalization and statistical analysis. Differentially expressed genes (DEGs) between groups at each time point or between time points within the group were revealed by t-test. Genes with p < 0.05 after Benjamini and Hochberg false discovery rate correction for multiple hypothesis testing were considered as significant DEGs. We found that (1) the Ingenuity Pathway Analysis (IPA) revealed significant enrichment of DEGs in multiple pathways, especially those responding to oxidative stress, in homozygous Cops8-CKO hearts at both 2 and 3 weeks, corroborating the occurrence of massive cardiomyocyte necrosis at 3 weeks; (2) the decreases in multiple CRL SR proteins were associated with decreased transcript levels; and (3) enrichment of DEGs in the chromatin remodeling pathway and the microtubule motility and vesicle trafficking pathways.Conclusions: Our data are consistent with the notion that Cops8/CSN plays a role in the transcriptional regulation of CRL SRs and in the redox and vesicle trafficking pathways.

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Section: Resultsmentioning

confidence: 99%

Murine Myocardial Transcriptome Analysis Reveals a Critical Role of COPS8 in the Gene Expression of Cullin-RING Ligase Substrate Receptors and Redox and Vesicle Trafficking Pathways

et al. 2017

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“…Embryonic arrest at the 2-cell stage after co-injection of anti-COPS3 antibody with or without Trim21 mRNA is a phenotype which is reminiscent of so-called maternal-effect genes, such as Mater (Nlrp5), Zar1, Hsf1 and Brg1 (Smarca4) [43][44][45][46] . However, Cops3 is known to function in germinal-vesicle mouse oocytes to support meiosis 17 , whereas mutations of maternal-effect genes should affect the embryogenesis without affecting the gametogenesis (neither oogenesis nor spermatogenesis) 47 . Looking for the main cause of the 2-cell arrest following immunological COPS3-inactivation proved challenging because it turned out that COPS3 is involved in numerous molecular functions of many different cellular processes.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to this variety of roles in the soma, the roles of COP9 or its subunits are still poorly characterized in the mammalian germline. Current knowledge points at germline stem cell survival 15,16 , meiosis 17 and epiblast survival in the postimplantation embryo 6 , while the preimplantation embryo seems unaffected. We were, therefore, surprised to find that when 2-cell mouse embryos were bisected and followed up in development, the Cops3 mRNA inter-blastomere difference correlated, three days later, with the number of epiblast cells found in monozygotic twin blastocysts derived from the sister blastomeres 5,18,19 .…”

Section: Introductionmentioning

confidence: 99%

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

Israel

Drexler

Fuellen

et al. 2021

Preprint

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Investigations of genes required in early mammalian development are complicated by protein deposits of maternal products, which continue to operate after the gene locus has been disrupted. This leads to an underestimation of the number of genes known to be needed during the embryonic phase of cellular totipotency (up to the 4-cell stage). Here, we expose a critical role of the gene Cops3 by showing that it protects genome integrity during the 2-cell stage of mouse embryo development, in contrast to the previous functional assignment at postimplantation. This new role is mediated by a large, stable and hitherto overlooked deposit of maternal protein. Since protein abundance and stability defeat prospects of DNA- or RNA-based gene inactivation, we adopted a protein strategy of gene inactivation: antigen masking or TRIM21-mediated proteasomal degradation of COPS3. Both resulted in 2-cell embryo lethality, but the expected degradation remained outstanding, because the major fraction of the total COPS3 is secluded in a submembrane cortical rim that withstands extraction with detergent, thereby exposing a soluble vs. insoluble fraction of COPS3, which we ascribe with distinct functional properties. In mechanistic terms, transcriptomic and metabolic analyses reveal that soluble COPS3 is involved in several processes, which, however, converge on DNA endoreduplication and the accumulation of DNA strand breaks in the 2-cell nucleus, where the minor soluble fraction of COPS3 is placed. Thus, we have shown the critical role of maternal protein deposits in development, and we have also highlighted the distinction between the site of accumulation (cell cortex) and point of use (nucleus), which is a dimension of the protein-based strategies of gene inactivation not yet fully appreciated.

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“…Its expression increases during oocyte maturation and it is required for oocyte meiosis. COPS5 also regulates the maturation-promoting factor (MPF) activity [31]. Furthermore, progesterone receptor (PGR), which regulates ovulation, lies downstream of COPS5 [32,33].…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of DUB Genes in Ovarian Cells Treated with Di-2-Ethylhexyl Phthalate

Lee

Park

Choi

et al. 2020

IJMS

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Premature ovarian failure (POF) is defined as loss of ovarian function in women less than 40 years of age. The causes of POF are diverse and include environmental factors. Di-2-ethylhexyl phthalate (DEHP) is one factor that may cause POF. The ubiquitin-proteasome system maintains intracellular balance by promoting or inhibiting protein degradation. To investigate the differential expressions of deubiquitinating enzyme (DUB) genes in patients with POF, we developed two in vitro POF models by treating A2780 or OVCAR5 with DEHP. Using these models, a multiplex RT-PCR system for DUB genes was applied to identify biomarkers by comparing expression patterns and DUB mRNA levels; multiplex RT-PCR results were validated by qRT-PCR and Western blotting analyses. Observed differential expression levels of several DUB genes including USP12, COPS5, ATXN3L, USP49, and USP34 in A2780 and OVCAR5 cells at the mRNA and protein levels suggest that they should be investigated as potential biomarkers of POF.

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Function of COP9 Signalosome in Regulation of Mouse Oocytes Meiosis by Regulating MPF Activity and Securing Degradation

Cited by 11 publications

References 54 publications

Murine Myocardial Transcriptome Analysis Reveals a Critical Role of COPS8 in the Gene Expression of Cullin-RING Ligase Substrate Receptors and Redox and Vesicle Trafficking Pathways

Murine Myocardial Transcriptome Analysis Reveals a Critical Role of COPS8 in the Gene Expression of Cullin-RING Ligase Substrate Receptors and Redox and Vesicle Trafficking Pathways

A Critical Role for The COP9 Signalosome Subunit 3 as A Gatekeeper of Genome Integrity in 2-Cell Mouse Embryos

Differential Expression of DUB Genes in Ovarian Cells Treated with Di-2-Ethylhexyl Phthalate

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