Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1125053 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR29444021_1.fastq.gz | Fastqsanger.gz | |||
| SRR29444021_2.fastq.gz | Fastqsanger.gz | |||
| SRR29444023_1.fastq.gz | Fastqsanger.gz | |||
| SRR29444023_2.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Precise control of protein ubiquitination is essential for brain development, and hence, disruption of ubiquitin signaling networks can lead to neurological disorders. Mutations of the deubiquitinase USP7 cause the Hao-Fountain syndrome (HAFOUS), characterized by developmental delay, intellectual disability, autism, and aggressive behavior. These neurological and behavioral manifestations indicate important unknown roles of USP7 specificially in the nervous system. Here, we report that conditional deletion of USP7 in excitatory neurons in the mouse forebrain triggers diverse phenotypes including growth delay, sensorimotor deficits, learning and memory impairment, and aggressive behavior, resembling clinical features of HAFOUS. USP7 deletion induces neuronal apoptosis in a manner dependent of the tumor suppressor p53. However, most behavioral abnormalities in USP7 conditional mice persist despite p53 loss. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Integrated proteomics and subsequent ubiquitin biochemical analysis identify the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Consistent with the role of Ppil4 in RNA splicing, loss of USP7 disrupts splicing program of synaptic genes in the cerebral cortex. Improtantly, knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of USP7 loss on dendritic spines. These findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of HAFOUS and other neurodevelopmental disorders.
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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.
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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.
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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.
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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.
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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.
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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).
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Project description:B-cell acute lymphoblastic leukemia (B-ALL) is a hematological malignancy that remains a significant clinical challenge, highlighting the urgent need for novel therapeutic strategies. Here, we performed a high-throughput screen of compounds approved by the U.S. Food and Drug Administration (FDA) and identified albendazole (ABZ), a benzimidazole anthelmintic, as a potent anti-leukemic agent against B-ALL. ABZ demonstrated robust cytotoxicity in B-ALL cell lines and patient-derived samples while sparing normal hematopoietic cells, and significantly reduced leukemia burden and prolonged survival in both cell line-derived and patient-derived xenograft models. Mechanistically, ABZ induced ferroptosis, characterized by lipid peroxidation, glutathione depletion, and ROS accumulation. ABZ promoted the ubiquitin-proteasome-mediated degradation of glutathione peroxidase 4 (GPX4) through autophagy-dependent destabilization of the deubiquitinase ubiquitin-specific protease 7 (USP7). USP7 was shown to directly interact with and stabilize GPX4 by removing K48-linked ubiquitin chains, and both proteins were markedly overexpressed in B-ALL patient samples, correlating with poor survival. Notably, ABZ also downregulated PD-L1 expression in leukemia cells, enhancing the efficacy of CD19 chimeric antigen receptor T (CAR-T) cell therapy in vitro and in vivo. Our findings delineate a previously unrecognized USP7-GPX4 axis regulating ferroptosis and provide a rationale for clinical repurposing of ABZ, alone or in combination with immunotherapies, to improve outcomes in B-ALL.
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