Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The protease DDI2 regulates NRF1-metallothionein pathway in response to Cadmium toxicity in the liver

ABSTRACT: DNA-damage inducible 1 homolog 2 (DDI2) is an aspartic protease that cleaves and activates the transcription factor NRF1. Cellular models have shown that this pathway contributes to cell-stress adaption, for example, upon proteasome inhibition. However, DDI2 physiological function is unknown. Ddi2 Knock-out (KO) mice are embryonic lethal. However, we found that liver-specific Ddi2-KO animals are viable. We used comprehensive genetic analysis to identify the molecular pathways regulated by DDI2. We show that DDI2 mediates metallothionein (MT) expression in mouse and human hepatocytes in response to cadmium (Cd). Cd exposure inhibits the proteasome activity, resulting in NRF1 accumulation in the cytoplasm, followed by cleavage by DDI2 and translocation to the nucleus to activate MTs. Depleting DDI2 or NRF1 by CRISPR/Cas9 impaired MTs activation and sensitized the cells to Cd or cisplatin toxicity. This study identifies a new function for DDI2 that links proteasome homeostasis to heavy metal mediated toxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE198150 | GEO | 2022/10/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The protease DDI2 regulates NRF1-metallothionein pathway in response to Cadmium toxicity in the liver

Project description:The protease DDI2 regulates NRF1-metallothionein pathway in response to Cadmium toxicity in the liver

| PRJNA813869 | ENA

Chromatin binding of NRF1 after exposure to proteasome inhibitor

Project description:NRF1 was localized at promoter regions of almost all proteasome subunit genes

2018-07-01 | GSE108856 | GEO

Genome-wide mapping of NRF1 (NFE2L1) binding in HCT116 cells upon proteasome inhibition.

Project description:The maintenance of protein homeostasis is an essential characteristic of life. Transcription factor NRF1 (NFE2L1) has been reported to be activated by proteasome dysfunction, although the genome-wide target genes are poorly understood. Using ChIP-seq analysis, we found a potential association between NRF1 and autophagy. Our findings highlight the new activation mechanism of autophagy through gene regulation under proteasome dysfunction.

2023-03-19 | GSE227357 | GEO

Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways

Project description:A hallmark of neurodegenerative diseases such as Parkinson’s Disease is the progressive loss of proteostasis, leading to the conversion of misfolded proteins into aggregates and subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect and degrade misfolded proteins. Here, we find that aggregation burden dictates the activation of proteasome-dependent quality control pathways. Initial misfolded proteins, enriched in oligomers, utilize UBE3C-dependent proteasomal degradation, while higher aggregation levels, enriched in larger insoluble structures, activate the NRF1 transcription factor to increase proteasome subunit transcription, and subsequent degradation capacity of cells. The role of UBE3C and NRF1 in aggregation clearance may provide therapeutic targets aimed to preventing neurodegenerative disease.

2024-10-09 | PXD055227 | Pride

Absolute quantification analysis of ubiquitin chains attached to Nrf1 purified from NGLY1-KO cells overexpressing Nrf1-FLAG with HA-FBS2.

Project description:We examined ubiquitin-linkages on Nrf1 purified from cell lysates of NGLY1-KO cells overexpressing Nrf1-FLAG with HA-FBS2. The ubiquitin linkage types were quantified using the LC-MS/MS-based absolute quantification method, ubiquitin parallel reaction monitoring (Ub-AQUA/PRM).

2024-08-06 | PXD053753 | Pride

Expression data from NRF1 knockdown and/or MG132 treated HCT116 cells

Project description:Transcription factor NRF1 (NFE2L1) has been reported to be activated by proteasome disfunction, although the target genes are poorly understood. We used microarrays to identify NRF3-regulated gene expression network related to proteostasis.

2023-03-18 | GSE227232 | GEO

ER-trafficking triggers NRF1 ubiquitination to promote its proteolytic activation

Project description:The endoplasmic reticulum (ER) is a multifaceted organelle that plays an essential role in cellular processes such as protein folding, modification, and trafficking. It also acts as a proteostasis sensor and contributes to adaptation responses to maintain cellular homeostasis. The transcription factor NRF1 resides in the ER and is constantly transported from the ER to the cytosol for proteasomal degradation. However, when the proteasome function is defective, NRF1 escapes degradation and undergoes proteolytic cleavage by the protease DDI2, generating a transcriptionally active form that restores proteostasis, including proteasome function. Despite the importance of NRF1 in these processes, the mechanisms that regulate its proteolytic activation and transcriptional potential remain poorly understood. In this study, we utilized a functional molecular approach to elucidate the critical steps involved in NRF1 cleavage. Our results demonstrate that the ER is a crucial regulator of NRF1 function, orchestrating its ubiquitination by the ER-localized E3 ubiquitin ligase HRD1, a component of the ER-associated degradation (ERAD) pathway. Furthermore, we show that HRD1-mediated NRF1 ubiquitination is necessary for DDI2-mediated processing in cells. Notably, we found that the fusion of a ubiquitin moiety to NRF1 was sufficient to promote its proteolytic maturation by DDI2, thus bypassing the requirement for its trafficking to the ER. Our findings highlight the intricate mechanism by which NRF1 is activated by DDI2 and coordinates the transcriptional activity of an adaptation response in cells and suggest potential avenues for therapeutic interventions in conditions associated with proteasome impairment.

2023-09-05 | PXD041331 | Pride

Drivers of metallothionein-mediated detoxification of cadmium in C.elegans

Project description:Cadmium is toxic and intricate pathways linked to metallothioneins (MT) drive the detoxification process. Whist the mechanisms are well understood in mammalian systems, detailed knowledge is still elusive in invertebrates (which notably differ to mammalian systems). The model nematode Caenorhabditis elegans is ideally suited for assessing metallothionein mediates detoxification in invertebrates as is relatively short-lived, can be easily exposed and its genome is fully sequenced and widely annotated. The aim of the experiment was to identify new MT mediated target genes involved in Cd toxicosis. The global transcriptome was compared in wild type and a MT double knockout strain raised in the presence or absence of 30 µM Cd.

2014-06-01 | E-GEOD-29951 | biostudies-arrayexpress

Effect of depletion of NRF1 on gene expression in mouse PMs infected with VSV for 8 h

Project description:To investigate NRF1 in the regulation of the innate immunity, we isolated Mouse peritoneal macrophages in in wild-type and NRF1-KO mouse

2022-12-31 | GSE218960 | GEO

Chromatin binding of NRF1 after exposure to proteasome inhibitor

Project description:Chromatin binding of NRF1 after exposure to proteasome inhibitor

| PRJNA428954 | ENA