USP7 represses lineage differentiation genes in mouse embryonic stem cells by both catalytic and noncatalytic activities

Liu, Chao; Sun, Luwei; Tan, Yamin; Wang, Q. Tian; Luo, Tao; Li, Chenlu; Yao, Nan; Xie, Yuting; Yi, Xiao; Zhu, Yi; Guo, Tiannan; Ji, Junfeng

doi:10.1126/sciadv.ade3888

Cited by 7 publications

(3 citation statements)

References 69 publications

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“…We speculate that USP7 activity might affect FOXL2 recruitment to DNA, stabilizing this interaction and thus allowing the differentiation of granulosa cells in wild-type prepubertal ovaries. Because our ChIP-SICAP experiment allows for detection of proteins colocalizing on the same chromatin regions, it is also plausible that USP7 may not directly bind to FOXL2, but it could be enriched in the same chromatin regions, possibly contributing to gene regulation as shown in other systems, for example, mouse embryonic stem cells differentiation ( 97 ) and early adipogenesis ( 98 ). We noted that the Usp7 gene was expressed throughout ovarian development to similar levels as of Foxl2 .…”

Section: Discussionmentioning

confidence: 99%

FOXL2 interaction with different binding partners regulates the dynamics of ovarian development

Migale,

Neumann,

Mitter

et al. 2024

Sci. Adv.

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The transcription factor FOXL2 is required in ovarian somatic cells for female fertility. Differential timing of Foxl2 deletion, in embryonic versus adult mouse ovary, leads to distinctive outcomes, suggesting different roles across development. Here, we comprehensively investigated FOXL2’s role through a multi-omics approach to characterize gene expression dynamics and chromatin accessibility changes, coupled with genome-wide identification of FOXL2 targets and on-chromatin interacting partners in somatic cells across ovarian development. We found that FOXL2 regulates more targets postnatally, through interaction with factors regulating primordial follicle formation and steroidogenesis. Deletion of one interactor, ubiquitin-specific protease 7 ( Usp7 ), results in impairment of somatic cell differentiation, germ cell nest breakdown, and ovarian development, leading to sterility. Our datasets constitute a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.

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Section: Discussionmentioning

confidence: 99%

FOXL2 interaction with different binding partners regulates the dynamics of ovarian development

Migale,

Neumann,

Mitter

et al. 2024

Sci. Adv.

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“…At the same time, we know that USP7 is a deubiquitinating enzyme, and its deubiquitinating activity is usually explored in research to maintain protein stability. However, it has been reported that USP7 can interact with PcG proteins to regulate molecular transcription [ 78 ]. Thus, the regulation of NLGN3 by USP7 may not only indirectly promote NLGN3 transcription by stabilizing KPNB1 expression by deubiquitination.…”

Section: Discussionmentioning

confidence: 99%

Stabilization of KPNB1 by deubiquitinase USP7 promotes glioblastoma progression through the YBX1-NLGN3 axis

Li,

Zhang,

Feng

et al. 2024

J Exp Clin Cancer Res

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Background Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. It is an aggressive tumor characterized by rapid proliferation, diffuse tumor morphology, and poor prognosis. Unfortunately, current treatments, such as surgery, radiotherapy, and chemotherapy, are unable to achieve good outcomes. Therefore, there is an urgent need to explore new treatment targets. A detailed mechanistic exploration of the role of the nuclear pore transporter KPNB1 in GBM is lacking. This study demonstrated that KPNB1 regulated GBM progression through a transcription factor YBX1 to promote the expression of post-protrusion membrane protein NLGN3. This regulation was mediated by the deubiquitinating enzyme USP7. Methods A tissue microarray was used to measure the expression of KPNB1 and USP7 in glioma tissues. The effects of KPNB1 knockdown on the tumorigenic properties of glioma cells were characterized by colony formation assays, Transwell migration assay, EdU proliferation assays, CCK-8 viability assays, and apoptosis analysis using flow cytometry. Transcriptome sequencing identified NLGN3 as a downstream molecule that is regulated by KPNB1. Mass spectrometry and immunoprecipitation were performed to analyze the potential interaction between KPNB1 and YBX1. Moreover, the nuclear translocation of YBX1 was determined with nuclear-cytoplasmic fractionation and immunofluorescence staining, and chromatin immunoprecipitation assays were conducted to study DNA binding with YBX1. Ubiquitination assays were performed to determine the effects of USP7 on KPNB1 stability. The intracranial orthotopic tumor model was used to detect the efficacy in vivo. Results In this study, we found that the nuclear receptor KPNB1 was highly expressed in GBM and could mediate the nuclear translocation of macromolecules to promote GBM progression. Knockdown of KPNB1 inhibited the progression of GBM, both in vitro and in vivo. In addition, we found that KPNB1 could regulate the downstream expression of Neuroligin-3 (NLGN3) by mediating the nuclear import of transcription factor YBX1, which could bind to the NLGN3 promoter. NLGN3 was necessary and sufficient to promote glioma cell growth. Furthermore, we found that deubiquitinase USP7 played a critical role in stabilizing KPNB1 through deubiquitination. Knockdown of USP7 expression or inhibition of its activity could effectively impair GBM progression. In vivo experiments also demonstrated the promoting effects of USP7, KPNB1, and NLGN3 on GBM progression. Overall, our results suggested that KPNB1 stability was enhanced by USP7-mediated deubiquitination, and the overexpression of KPNB1 could promote GBM progression via the nuclear translocation of YBX1 and the subsequent increase in NLGN3 expression. Conclusion This study identified a novel and targetable USP7/KPNB1/YBX1/NLGN3 signaling axis in GBM cells.

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“…Consequently, expression of primitive endoderm-associated genes is hindered. Despite these findings, it remains to be established whether these newly identified functions of USP7 play a critical role in the early stages of embryonic development ( Liu et al, 2023 ) and whether USP7 is able to modulate other cellular processes in a non-catalytic manner.…”

Section: Non-catalytic Functions Of Dubs and Ubl Proteasesmentioning

confidence: 99%

In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases

Campos Alonso,

Knobeloch

2024

Front. Mol. Biosci.

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Proteases that cleave ubiquitin or ubiquitin-like proteins (UBLs) are critical players in maintaining the homeostasis of the organism. Concordantly, their dysregulation has been directly linked to various diseases, including cancer, neurodegeneration, developmental aberrations, cardiac disorders and inflammation. Given their potential as novel therapeutic targets, it is essential to fully understand their mechanisms of action. Traditionally, observed effects resulting from deficiencies in deubiquitinases (DUBs) and UBL proteases have often been attributed to the misregulation of substrate modification by ubiquitin or UBLs. Therefore, much research has focused on understanding the catalytic activities of these proteins. However, this view has overlooked the possibility that DUBs and UBL proteases might also have significant non-catalytic functions, which are more prevalent than previously believed and urgently require further investigation. Moreover, multiple examples have shown that either selective loss of only the protease activity or complete absence of these proteins can have different functional and physiological consequences. Furthermore, DUBs and UBL proteases have been shown to often contain domains or binding motifs that not only modulate their catalytic activity but can also mediate entirely different functions. This review aims to shed light on the non-catalytic, moonlighting functions of DUBs and UBL proteases, which extend beyond the hydrolysis of ubiquitin and UBL chains and are just beginning to emerge.

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USP7 represses lineage differentiation genes in mouse embryonic stem cells by both catalytic and noncatalytic activities

Cited by 7 publications

References 69 publications

FOXL2 interaction with different binding partners regulates the dynamics of ovarian development

FOXL2 interaction with different binding partners regulates the dynamics of ovarian development

Stabilization of KPNB1 by deubiquitinase USP7 promotes glioblastoma progression through the YBX1-NLGN3 axis

In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases

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