Insulin-degrading enzyme regulates mRNA processing and interacts with the CCR4-NOT complex
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ABSTRACT:
PROVIDER: PRJNA1272523 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33841695_1.fastq.gz | Fastqsanger.gz | |||
| SRR33841695_2.fastq.gz | Fastqsanger.gz |
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Project description:Insulin-degrading enzyme is a zinc metallo protease degrading low molecular weight substrates including insulin. Ubiquitous expression, high evolutionary conservation, upregulation of Ide in stress situations, and literature findings suggest a broader function of Ide in cell physiology and protein homeostasis that remains to be elucidated. We used proteomics and transcriptomics approaches searching for leads related to a broader role of Ide in protein homeostasis. We combined an analysis of the proteome and single-cell transcriptome of Ide+/+ and Ide-/- pancreatic islet cells with an examination of the interactome of human cytosolic Ide using proximity biotinylation. We observe an upregulation of pathways related to RNA processing, translation and splicing in Ide+/+ relative to Ide-/- islet cells. Corroborating these results and providing a potential mechanistic explanation, proximity biotinylation reveals interaction of Ide with several subunits of CCR4-NOT, a key mRNA deadenylase regulating gene expression "from birth to death". We propose a speculative model in which human and murine Ide and CCR4-NOT cooperate to control protein expression in proteotoxic and metabolic stress situations through cooperation between their deadenylase and protease functions.
2025-06-18 | GSE299071 | GEO
Project description:Insulin-degrading enzyme is zinc metallo protease degrading low molecular weight substrates including insulin. Ubiquitous expression, high evolutionary conservation, upregulation of Ide in stress situations, and various literature findings suggest a broader function of Ide in cell physiology and protein homeostasis that remains to be elucidated. We used proteomics and transcriptomics approaches searching for leads related to a broader role of Ide in protein homeostasis. We combined an analysis of the proteome and single-cell transcriptome of Ide+/+ and Ide-/- pancreatic islet cells with an examination of the interactome of human cytosolic Ide using proximity biotinylation. We observe an upregulation of pathways related to RNA processing and translation in Ide+/+ relative to Ide-/- islet cells. Corroborating these results and providing a potential mechanistic explanation, proximity biotinylation reveals interaction of Ide with several subunits of CCR4-NOT, a key complex and mRNA deadenylase regulating protein expression "from birth to death". We propose a speculative model in which Ide and CCR4-NOT cooperate to control and limit protein expression in proteotoxic and met-abolic stress situations through cooperation between their deadenylase and protease functions.
2025-06-16 | PXD060228 | Pride
Project description:Insulin degrading enzyme (IDE) is a major enzyme responsible for insulin degradation in the liver. The modulation of insulin degrading enzyme activity is hypothesized to be a link between T2DM and liver cancer. Results provide insight into role of IDE in proliferation and other cell functions.
2014-09-06 | GSE61142 | GEO
Project description:Insulin degrading enzyme (IDE) is a major enzyme responsible for insulin degradation in the liver. The modulation of insulin degrading enzyme activity is hypothesized to be a link between T2DM and liver cancer. Results provide insight into role of IDE in proliferation and other cell functions. HepG2 cells were transfected with 96nM siRNA for IDE or AllStars Negative Control siRNA (Qiagen) using Lipofectamine 2000 (Invitrogen). 16 h after transfection, cells were treated with 10 nM insulin (Sigma Aldrich) or vehicle for 24 h in serum starvation condition. Total RNA was extracted. For each of the 4 conditions, 3 biological replicates were included.
2014-09-06 | E-GEOD-61142 | biostudies-arrayexpress
Project description:Insulin-degrading enzyme (IDE) is a protein with proteolytic and non-proteolytic functions that regulates glucose homeostasis.We hypothesize that IDE deficiency alters glucagon signaling and thereby gluconeogenesis. To test this hypothesis we performed microarray studies in HepG2 cells with a complete deficiency of IDE gene. Results show that IDE deficiency led to upregulation of genes involved in cellular functions related to membranes, organelles and signaling receptors. We used microarrays to find genes whose expression is affected by the absence of IDE gene expression in hetapome human cells
2025-06-04 | GSE297588 | GEO
Project description:Expression data from Insulin Degrading Enzyme-Knocked Out hepatome human cells
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Project description:Insulin-degrading enzyme (IDE) is a highly conserved metalloprotease that is mainly localized in the cytosol. Although IDE can degrade insulin and some other low molecular weight substrates efficiently, its ubiquitous expression suggests additional functions supported by experimental findings, such as a role in stress responses and cellular protein homeostasis. The translation of a long full-length IDE transcript has been reported to result in targeting to mitochondria, but the role of IDE in this compartment is unknown. To obtain initial leads on the function of IDE in mitochondria, we used a proximity biotinylation approach to identify proteins interacting with wild-type and protease-dead IDE targeted to the mitochondrial matrix. We find that IDE interacts with multiple mitochondrial ribosomal proteins as well as with proteins involved in the synthesis and assembly of mitochondrial complex I and IV. The mitochondrial interactomes of wild type and mutant IDE are highly similar and do not reveal any likely proteolytic IDE substrates. We speculate that IDE could adopt similar additional non-proteolytic functions in mitochondria as in the cytosol, acting as a chaperone and contributing to protein homeostasis and stress responses.
| S-EPMC10296325 | biostudies-literature
Project description:Oxidative stress has a ubiquitous role in neurodegenerative diseases and oxidative damage in specific regions of the brain is associated with selective neurodegeneration. We previously reported that Alzheimer disease (AD) model mice showed decreased insulin-degrading enzyme (IDE) levels in the cerebrum and accelerated phenotypic features of AD when crossbred with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice. To further investigate the role of chronic oxidative stress in AD pathophysiology, we performed DNA microarray analysis using young and aged wild-type mice and aged Ttpa-/- mice. Among the genes whose expression changed dramatically was Phospholipase A2 group 3 (Pla2g3); Pla2g3 was identified because of its expression profile of cerebral specific up-regulation by chronic oxidative stress in silico and in aged Ttpa-/- mice. Immunohistochemical studies also demonstrated that human astrocytic Pla2g3 expression was significantly increased in human AD brains compared with control brains. Moreover, transfection of HEK293 cells with human Pla2g3 decreased endogenous IDE expression in a dose-dependent manner. Our findings show a key role of Pla2g3 on the reduction of IDE, and suggest that cerebrum specific increase of Pla2g3 is involved in the initiation and/or progression of AD.
2015-11-20 | GSE75047 | GEO
Project description:Oxidative stress has a ubiquitous role in neurodegenerative diseases and oxidative damage in specific regions of the brain is associated with selective neurodegeneration. We previously reported that Alzheimer disease (AD) model mice showed decreased insulin-degrading enzyme (IDE) levels in the cerebrum and accelerated phenotypic features of AD when crossbred with alpha-tocopherol transfer protein knockout (Ttpa-/-) mice. To further investigate the role of chronic oxidative stress in AD pathophysiology, we performed DNA microarray analysis using young and aged wild-type mice and aged Ttpa-/- mice. Among the genes whose expression changed dramatically was Phospholipase A2 group 3 (Pla2g3); Pla2g3 was identified because of its expression profile of cerebral specific up-regulation by chronic oxidative stress in silico and in aged Ttpa-/- mice. Immunohistochemical studies also demonstrated that human astrocytic Pla2g3 expression was significantly increased in human AD brains compared with control brains. Moreover, transfection of HEK293 cells with human Pla2g3 decreased endogenous IDE expression in a dose-dependent manner. Our findings show a key role of Pla2g3 on the reduction of IDE, and suggest that cerebrum specific increase of Pla2g3 is involved in the initiation and/or progression of AD. Gene expression in cerebral cortex and cerebellum of mice were determined using Agilent chips. To ensure higher quality results in gene expression data, we conducted microarrays on 4 mice per group. Young mice were 2 months old and the other aged mice were 29 months old at the time of use. Data were standardized using global normalization and pro-cessed by R-program. An absolute fold change threshold of greater than 1.5 was required to be considered for further analyses. Expression values were in log2 scale.
2015-11-20 | E-GEOD-75047 | biostudies-arrayexpress
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