Cardiac p62/Sqstm1 maintains Nrf2 protein levels and protects from oxidative stress
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ABSTRACT:
PROVIDER: PRJNA802961 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17867728_1.fastq.gz | Fastqsanger.gz | |||
| SRR17867728_2.fastq.gz | Fastqsanger.gz | |||
| SRR17867729_1.fastq.gz | Fastqsanger.gz | |||
| SRR17867729_2.fastq.gz | Fastqsanger.gz | |||
| SRR17867730_1.fastq.gz | Fastqsanger.gz |
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Project description:Squestosome 1 (SQSTM1), also known as p62, is a multi-functional adaptor protein known for its pleotropic roles in autophagy, proteostasis, inflammation and cancer. Recently, p62 has emerged as an important modulator of protein quality control and aging. However, its role in the heart is not well understood. Our understanding of the role of p62 in the heart has been limited to the indirect assessment of its function in the setting of autophagy inhibition or proteotoxic stress. However, whether p62 is required to maintain cardiac function at rest or in response to stress has not been explored. Here we investigated the functional consequence of cardiac p62 deletion in the absence of other contributing phenotypic and systemic factors observed in the whole-body p62 deleted mice. Lack of cardiomyocytes p62 precipitated cardiac aging in mice and was associated with reduced contractile function and a progressive development of cardiac hypertrophy and fibrosis. Transcriptomic analysis of p62-deleted heart revealed a selective impairment in Nrf2 transcription, which was confirmed in the hearts of p62cKO mice. We further showed that absence of p62 in adult mice resulted in excessive oxidative stress and cell death when mice were rendered hypoxic. To gain mechanistic insights, we employed loss and gain of p62 function in H9c2 cardiomyoblasts and showed a sustained reduction in Nrf2 protein expression, nuclear translocation and transcriptional activity in p62-deficient cells. Mechanistically, p62-deficient cells exhibited an increase in proteasome-mediated Nrf2 degradation. In contrast, gain of p62 function led to Nrf2 stabilization and transcriptional activity.
2023-12-31 | GSE196019 | GEO
Project description:These are the results of the iCLIP experiment for p62/SQSTM1 in Human Huh-7 cells treated with DMSO. We used iCLIP method to identify the RNA targets of p62 and nucleotide positions of the p62 interaction on RNA. We used 2 replicates and 2 different antibodies against endogenous p62 to enrich protein/RNA complexes. cDNAs were tagged with iCLIP composite barcodes (e.g. NNNTTGTNN) which contain 4 sample-encoding bases (e.g. TTGT) and and 5 random bases (noted with N in NNNTTGTNN example) which serve as unique molecular identifiers to post-filter PCR duplicates. These composite barcodes are found in the read headers (after last colon ':' character) of submitted fastq files.
2018-03-31 | E-MTAB-4894 | biostudies-arrayexpress
Project description:We used microarrays to detail the programme of gene expression in control or p62/SQSTM1-silenced A549 cells.
2022-07-21 | GSE208588 | GEO
Project description:Gene expression in p62/SQSTM1-silenced A549 cells.
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Project description:p62/SQSTM1 iCLIP in Human Huh-7 cells
| PRJEB19002 | ENA
Project description:Neurodegenerative disorders are an increasingly common and irreversible burden on society, often affecting the ageing population, but their aetiology and disease mechanisms are poorly understood. Studying monogenic neurodegenerative diseases, with known genetic cause, provides an opportunity to understand cellular mechanisms also affected in more complex disorders. We recently reported that loss-of-function mutations in the autophagy adaptor protein, SQSTM1/p62, lead to a slowly progressive neurodegenerative disease presenting in childhood. To further elucidate the neuronal involvement, we studied the cellular consequences of loss of p62 in a neuroepithelial stem (NES) cell model and differentiated neurones, derived from reprogrammed p62 patient cells, or by CRISPR/Cas9-directed gene editing in NES cells. Transcriptomic and proteomic analyses suggest that p62 is essential for neuronal differentiation by controlling the metabolic shift from aerobic glycolysis to oxidative phosphorylation required for neuronal maturation. This shift is blocked by the failure to sufficiently downregulate lactate dehydrogenase expression due to the loss of p62, possibly through impaired Hif-1α downregulation and increased sensitivity to oxidative stress. The findings implicate an important role for p62 in neuronal energy metabolism and particularly in the regulation of the shift between glycolysis and oxidative phosphorylation, required for normal neurodifferentiation.
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Project description:p62/SQSTM1 was identified as a modulator of metastatic genes selectively enriched in melanoma in autophagy independent manner. iTRAQ quantitative proteomic approach was performed in melanoma cell lines (SK-Mel-103 and UACC-62) deficient for p62 to identify downstream effectors of p62. Similar studies were performed for ATG5, a core component of autophagy, as a reference for autophagy-associated changes in protein abundance. Additionally, melanoma cells were subjected to affinity purification (AP-MS) to identify the interactors of p62. Overall, these studies underscore a novel unexpected role of p62 regulating the stability of prometastatic factors via the interaction with RNA Binding Proteins, thus leading to the inhibition of protein translation.
2022-02-28 | PXD006650 | Pride
Project description:Cancer-derived loss-of-function mutations in the KEAP1 tumor suppressor gene stabilize the NRF2 transcription factor, resulting in a pro-survival gene expression program that alters cellular metabolism and neutralizes oxidative stress. In a previous study of KEAP1 mutations observed in lung cancer, we classified 40% of the mutations as ‘superbinders’ (superbinders). These mutants bind and ubiquitylate NRF2 but do not promote NRF2 degradation. Here, we further investigated the molecular mechanism(s) driving the superbinder phenotype. BioID-based quantitative proteomic analysis of the R320Q and R470C superbinder mutations revealed increased co-complexed NRF2 without significant alteration to other KEAP1-associated proteins, including CUL3, VCP, and several ubiquitin receptors within the proteasome lid. Dynamic simulation modeling and limited proteolysis analyses suggest that superbinder mutations stabilize residues in KEAP1 that contact NRF2. In cells, KEAP1 R320Q and R470C mutants co-localize with NRF2, p62/SQSTM1 and polyubiquitin in spherical clusters that rapidly fuse and dissolve; KEAP1-NRF2 localization to these clusters requires p62. Expression of R320Q and R470C in lung cancer cells provided resistance to the reactive oxygen species-inducing drug bleomycin. We present a model wherein superbinder mutations alter the conformational dynamics of the KEAP1-NRF2 complex to alter the cycling of KEAP1 between open and closed conformations, thus inhibiting NRF2 degradation.
2018-11-07 | PXD008411 | Pride
Project description:Hepatic stellate cells (HSC) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSC inhibits liver inflammation and fibrosis. Here we show that p62/SQSTM1, a protein that is upregulated in liver parenchymal cells but downregulated in HCC-associated HSC, negatively regulates HSC activation. Total body or HSC-specific p62 ablation potentiates HSC activation and enhances inflammation, fibrosis and HCC progression. We demonstrate that p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target genes recruitment. Loss of p62 in HSC impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSC, whose activation supports HCC development.
2016-11-23 | GSE78760 | GEO
Project description:p62/SQSTM1 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCC). Although p62 was proposed to participate in formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression level in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, c-Myc induction and protection of HCC-initiating cells from oxidative stress-induced death.
2016-11-23 | GSE77323 | GEO