Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1125053 | ENA |
REPOSITORIES: ENA
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Project description:Individuals with genetic elimination of MLKL exhibit an increased susceptibility to neurodegenerative diseases like Alzheimer’s disease (AD). However, the specific mechanism behind this relationship is not yet fully understood. Here, we initially observed significant compromise in autophagy in the brains of MLKL knockout (KO) mice, as evidenced by the down-regulation of autophagy-initiation proteins Beclin1 and ULK1. To elucidate the mechanism by which MLKL, primarily a cytosolic protein, regulates the protein levels of Beclin1 and ULK1, we performed a proteomic screening of MLKL-association proteins and identified UBA52 as the binding partner under physiological conditions. Loss of MLKL induces a decrease in ubiquitin levels by preventing UBA52 from producing ubiquitin and the C-terminal ribosomal protein L40. Furthermore, we demonstrated that in the brain, the deubiquitinase (DUB) USP7 mediates the processing of UBA52, which is regulated by MLKL. Knock down (KD) of USP7 or UBA52 showed similar effects on autophagy and ubiquitin levels as MLKL KD/KO. Moreover, our results indicated that the reduction of Beclin1 and ULK1 upon MLKL loss is attributed to a decrease in their lysine 63 (K63)-linked polyubiquitination. Additionally, single-nucleus RNA sequencing revealed that the loss of MLKL resulted in the disruption of multiple neurodegenerative disease-related pathways, including those associated with AD. These results were consistent with the observation of cognitive impairment in MLKL KO mice and exacerbation of AD pathologies in an AD mouse model with MLKL deletion. Taken together, our findings demonstrate that MLKL-USP7-UBA52 signaling is required for autophagy in brain through maintaining ubiquitin homeostasis, and highlight the contribution of MLKL loss-induced ubiquitin deficits to the development of neurodegeneration. Thus, the maintenance of adequate levels of ubiquitin may provide a novel perspective to protect individuals from multiple neurodegenerative diseases through regulating autophagy.
2025-01-29 | GSE270139 | GEO
Project description:Ubiquitin Specific Protease 7 (USP7), also named as herpesvirus-associated ubiquitin-specific protease (HAUSP), is one of the most abundant deubiquitinase and plays multifaceted roles in many cellular functions, including the protein homeostasis, DNA repair, gene transcription, and oncogenic pathways. To investigate the role of USP7 in p53-deficient lung cancer cells, the CRISPR/Cas9-mediated gene editing was employed to inactivate the USP7 locus in H1299 cells. The alterations of transcriptional enhancers and gene expression were analyzed by H3K27ac ChIP-seq and RNA-seq, respectively, in wildtype and USP7-KO H1299 lung cancer cells.
2021-09-16 | GSE172506 | GEO
Project description:USP7, a ubiquitin-specific peptidase (USP), plays an important role in many cellular processes through its catalytic deubiquitination of various substrates. However, its nuclear function to regulate gene expression in mouse embryonic stem cells (mESCs) remains largely unknown. Here, we report that USP7 maintains mESCs identity through both catalytic activity-dependent and -independent repression of lineage differentiation genes. Usp7 depletion attenuates SOX2 level and derepresses lineage differentiation genes thereby compromising mESCs identity. Mechanistically, USP7 deubiquitinates and stabilizes SOX2 to repress mesoendodermal (ME) lineage genes. Moreover, USP7 assembles into RYBP-variant polycomb repressive complex 1 (vPRC1) and contributes to Polycomb chromatin domain-mediated repression of ME lineage genes in a catalytic activity-dependent manner. However, USP7 deficient in its deubiquitination function is able to maintain RYBP binding on chromatin to represses primitive endoderm-associated genes in mESCs. Overall, our study demonstrates that USP7 harbors both catalytic and non-catalytic scaffold activity to repress lineage differentiation genes thereby revealing a previously unrecognized role in controlling gene expression and maintaining mESCs identity.
2023-08-08 | GSE197427 | GEO
Project description:USP7, a ubiquitin-specific peptidase (USP), plays an important role in many cellular processes through its catalytic deubiquitination of various substrates. However, its nuclear function to regulate gene expression in mouse embryonic stem cells (mESCs) remains largely unknown. Here, we report that USP7 maintains mESCs identity through both catalytic activity-dependent and -independent repression of lineage differentiation genes. Usp7 depletion attenuates SOX2 level and derepresses lineage differentiation genes thereby compromising mESCs identity. Mechanistically, USP7 deubiquitinates and stabilizes SOX2 to repress mesoendodermal (ME) lineage genes. Moreover, USP7 assembles into RYBP-variant polycomb repressive complex 1 (vPRC1) and contributes to Polycomb chromatin domain-mediated repression of ME lineage genes in a catalytic activity-dependent manner. However, USP7 deficient in its deubiquitination function is able to maintain RYBP binding on chromatin to represses primitive endoderm-associated genes in mESCs. Overall, our study demonstrates that USP7 harbors both catalytic and non-catalytic scaffold activity to repress lineage differentiation genes thereby revealing a previously unrecognized role in controlling gene expression and maintaining mESCs identity.
2023-08-08 | GSE197157 | GEO
Project description:Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders. As a key modulator of brain homeostasis, it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here, we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Remarkably, systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity via on-demand degradation of glutamate receptors. Collectively, this study reveals a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a novel antidepressant strategy.
2025-01-20 | GSE287308 | GEO
Project description:Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders. As a key modulator of brain homeostasis, it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here, we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Remarkably, systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity via on-demand degradation of glutamate receptors. Collectively, this study reveals a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a novel antidepressant strategy.
2025-01-20 | GSE287175 | GEO
Project description:Ubiquitin Specific Peptidase 7 (USP7) is a deubiquitinase of several important regulatory proteins, and important regulator of TGFb pathway. To investigate their role in cell signaling, we analyzed global mRNA levels in HEK293T cells that were knocked down with shRNAs against USP7 and non-targeting control (CTRL).
2020-10-18 | GSE139094 | GEO
Project description:USP7, a ubiquitin-specific peptidase (USP), plays an important role in many cellular processes through its catalytic deubiquitination of various substrates. However, its nuclear function to shape the transcriptional network in mouse embryonic stem cells (mESCs) remains poorly understood. Here, we report that USP7 maintains mESCs identity through both catalytic activity-dependent and -independent repression of lineage differentiation genes. Usp7 depletion attenuates SOX2 level and derepresses lineage differentiation genes thereby compromising mESCs pluripotency. Mechanistically, USP7 deubiquitinates and stabilizes SOX2 to repress mesoendodermal (ME) lineage genes. Moreover, USP7 assembles into RYBP-variant Polycomb repressive complex 1 and contributes to Polycomb chromatin-mediated repression of ME lineage genes in a catalytic activity-dependent manner. Importantly, USP7 deficient in its deubiquitination function is able to maintain RYBP binding to chromatin for repressing primitive endoderm-associated genes. Overall, our study demonstrates that USP7 harbors both catalytic and non-catalytic activity to repress different lineage differentiation genes thereby revealing a previously unrecognized role in controlling gene expression for maintaining mESCs identity.
2023-07-20 | PXD039633 | Pride
Project description:The Ccr4-Not complex containing the Not4 ubiquitin ligase regulates gene transcription and mRNA decay, yet it also has poorly defined roles in translation, proteostasis, and endolysosomal-dependent nutrient signaling. To define how Ccr4-Not mediated ubiquitin signaling regulates these additional processes, we performed quantitative proteomics in the yeast Saccharomyces cerevisiae lacking the Not4 ubiquitin ligase and in cells overexpressing either wild-type or functionally inactive ligase. Herein, we provide evidence that both increased and decreased Ccr4-Not ubiquitin signaling disrupts ribosomal protein (RP) homeostasis independently of reduced RP mRNA changes or reductions in known Not4 ribosomal substrates. Surprisingly, we also find that Ccr4-Not inhibits 40S ribosomal autophagy through Not4-dependent ubiquitin signaling and the additional Ccr4 subunit. This 40S autophagy is independent of canonical Atg7-dependent macroautophagy, thus indicating microautophagy activation is responsible. Furthermore, the Not4 ligase genetically interacts with endolysosomal pathway effectors to control both RP expression and 40S autophagy efficiency. Overall, we demonstrate that balanced Ccr4-Not ligase activity maintains RP homeostasis, and that Ccr4-Not ubiquitin signaling interacts with the endolysosomal pathway to regulate RP expression and inhibit 40S ribosomal autophagy.
2024-10-17 | PXD044420 | Pride