scholarly journals CALHM1 ion channel elicits amyloid-  clearance by insulin-degrading enzyme in cell lines and in vivo in the mouse brain

2015 ◽  
Vol 128 (13) ◽  
pp. 2330-2338 ◽  
Author(s):  
V. Vingtdeux ◽  
P. Chandakkar ◽  
H. Zhao ◽  
L. Blanc ◽  
S. Ruiz ◽  
...  
Keyword(s):  
Ion Channel ◽  
Cell Lines ◽  
Mouse Brain ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme

scholarly journals Evolutionary Origin of Insulin-Degrading Enzyme and Its Subcellular Localization and Secretion Mechanism: A Study in Microglial Cells

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 227
Author(s):  
Miriam Corraliza-Gómez ◽  
Concepción Lillo ◽  
Irene Cózar-Castellano ◽  
Eduardo Arranz ◽  
Diego Sanchez ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Phylogenetic Analyses ◽  
In Silico Analysis ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Raft Domains ◽  
The Brain ◽  
Silico Analysis

The insulin-degrading enzyme (IDE) is a zinc-dependent metalloendopeptidase that belongs to the M16A metalloprotease family. IDE is markedly expressed in the brain, where it is particularly relevant due to its in vitro amyloid beta (Aβ)-degrading activity. The subcellular localization of IDE, a paramount aspect to understand how this enzyme can perform its proteolytic functions in vivo, remains highly controversial. In this work, we addressed IDE subcellular localization from an evolutionary perspective. Phylogenetic analyses based on protein sequence and gene and protein structure were performed. An in silico analysis of IDE signal peptide suggests an evolutionary shift in IDE exportation at the prokaryote/eukaryote divide. Subcellular localization experiments in microglia revealed that IDE is mostly cytosolic. Furthermore, IDE associates to membranes by their cytoplasmatic side and further partitions between raft and non-raft domains. When stimulated, microglia change into a secretory active state, produces numerous multivesicular bodies and IDE associates with their membranes. The subsequent inward budding of such membranes internalizes IDE in intraluminal vesicles, which later allows IDE to be exported outside the cells in small extracellular vesicles. We further demonstrate that such an IDE exportation mechanism is regulated by stimuli relevant for microglia in physiological conditions and upon aging and neurodegeneration.

scholarly journals Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria

2004 ◽  
Vol 383 (3) ◽  
pp. 439-446 ◽  
Author(s):  
Malcolm A. LEISSRING ◽  
Wesley FARRIS ◽  
Xining WU ◽  
Danos C. CHRISTODOULOU ◽  
Marcia C. HAIGIS ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Late Onset ◽  
Amyloid Β ◽  
Type Ii Diabetes Mellitus ◽  
Allelic Association ◽  
Amyloid Β Peptide ◽  
Mitochondrial Targeting ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme

IDE (insulin-degrading enzyme) is a widely expressed zinc-metallopeptidase that has been shown to regulate both cerebral amyloid β-peptide and plasma insulin levels in vivo. Genetic linkage and allelic association have been reported between the IDE gene locus and both late-onset Alzheimer's disease and Type II diabetes mellitus, suggesting that altered IDE function may contribute to some cases of these highly prevalent disorders. Despite the potentially great importance of this peptidase to health and disease, many fundamental aspects of IDE biology remain unresolved. Here we identify a previously undescribed mitochondrial isoform of IDE generated by translation at an in-frame initiation codon 123 nucleotides upstream of the canonical translation start site, which results in the addition of a 41-amino-acid N-terminal mitochondrial targeting sequence. Fusion of this sequence to the N-terminus of green fluorescent protein directed this normally cytosolic protein to mitochondria, and full-length IDE constructs containing this sequence were also directed to mitochondria, as revealed by immuno-electron microscopy. Endogenous IDE protein was detected in purified mitochondria, where it was protected from digestion by trypsin and migrated at a size consistent with the predicted removal of the N-terminal targeting sequence upon transport into the mitochondrion. Functionally, we provide evidence that IDE can degrade cleaved mitochondrial targeting sequences. Our results identify new mechanisms regulating the subcellular localization of IDE and suggest previously unrecognized roles for IDE within mitochondria.

Cloning, expression and characterization of insulin-degrading enzyme from tomato (Solanum lycopersicum)

2008 ◽  
Vol 389 (1) ◽  
pp. 91-98 ◽  
Author(s):  
Yoann Huet ◽  
Jochen Strassner ◽  
Andreas Schaller
Keyword(s):  
Solanum Lycopersicum ◽  
Catalytic Efficiency ◽  
Biochemical Properties ◽  
Amyloid Peptide ◽  
Energy Status ◽  
Insulin Degrading Enzyme ◽  
Peptide Bonds ◽  
Degrading Enzyme ◽  
Β Amyloid Peptide

Abstract A cDNA encoding insulin-degrading enzyme (IDE) was cloned from tomato (Solanum lycopersicum) and expressed in Escherichia coli in N-terminal fusion with glutathione S-transferase. GST-SlIDE was characterized as a neutral thiol-dependent metallopeptidase with insulinase activity: the recombinant enzyme cleaved the oxidized insulin B chain at eight peptide bonds, six of which are also targets of human IDE. Despite a certain preference for proline in the vicinity of the cleavage site, synthetic peptides were cleaved at apparently stochastic positions indicating that SlIDE, similar to IDEs from other organisms, does not recognize any particular amino acid motif in the primary structure of its substrates. Under steady-state conditions, an apparent K m of 62±7 μm and a catalytic efficiency (k cat/K m) of 62±15 mm -1 s-1 were determined for Abz-SKRDPPKMQTDLY(NO3)-NH2 as the substrate. GST-SlIDE was effectively inhibited by ATP at physiological concentrations, suggesting regulation of its activity in response to the energy status of the cell. While mammalian and plant IDEs share many of their biochemical properties, this similarity does not extend to their function in vivo, because insulin and the β-amyloid peptide, well-established substrates of mammalian IDEs, as well as insulin-related signaling appear to be absent from plant systems.

scholarly journals Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues

2019 ◽  
Vol 316 (1) ◽  
pp. E106-E120 ◽  
Author(s):  
Joshua A. Kulas ◽  
Whitney F. Franklin ◽  
Nicholas A. Smith ◽  
Gunjan D. Manocha ◽  
Kendra L. Puig ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Ex Vivo ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Type I ◽  
Insulin Degrading Enzyme ◽  
Peripheral Tissues ◽  
Degrading Enzyme ◽  
Bodies Of Evidence

The amyloid precursor protein (APP) is a type I transmembrane glycoprotein widely studied for its role as the source of β-amyloid peptide, accumulation of which is causal in at least some cases of Alzheimer’s disease (AD). APP is expressed ubiquitously and is involved in diverse biological processes. Growing bodies of evidence indicate connections between AD and somatic metabolic disorders related to type 2 diabetes, and App−/− mice show alterations in glycemic regulation. We find that App−/− mice have higher levels of insulin-degrading enzyme (IDE) mRNA, protein, and activity compared with wild-type controls. This regulation of IDE by APP was widespread across numerous tissues, including liver, skeletal muscle, and brain as well as cell types within neural tissue, including neurons, astrocytes, and microglia. RNA interference-mediated knockdown of APP in the SIM-A9 microglia cell line elevated IDE levels. Fasting levels of blood insulin were lower in App−/− than App+/+ mice, but the former showed a larger increase in response to glucose. These low basal levels may enhance peripheral insulin sensitivity, as App−/− mice failed to develop impairment of glucose tolerance on a high-fat, high-sucrose (“Western”) diet. Insulin levels and insulin signaling were also lower in the App−/− brain; synaptosomes prepared from App−/− hippocampus showed diminished insulin receptor phosphorylation compared with App+/+ mice when stimulated ex vivo. These findings represent a new molecular link connecting APP to metabolic homeostasis and demonstrate a novel role for APP as an upstream regulator of IDE in vivo.

scholarly journals 17β-Estradiol and Progesterone Regulate Expression of β-Amyloid Clearance Factors in Primary Neuron Cultures and Female Rat Brain

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5467-5479 ◽  
Author(s):  
Anusha Jayaraman ◽  
Jenna C. Carroll ◽  
Todd E. Morgan ◽  
Sharon Lin ◽  
Liqin Zhao ◽  
...  
Keyword(s):  
Sex Steroid ◽  
Female Rat ◽  
Converting Enzyme ◽  
Primary Neuron ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
17Β Estradiol ◽  
Β Amyloid ◽  
Aβ Clearance

Abstract The accumulation of β-amyloid protein (Aβ) is a key risk factor in the development of Alzheimer's disease. The ovarian sex steroid hormones 17β-estradiol (E2) and progesterone (P4) have been shown to regulate Aβ accumulation, although the underlying mechanism(s) remain to be fully elucidated. In this study, we investigate the effects of E2 and P4 treatment on the expression levels of Aβ clearance factors including insulin-degrading enzyme, neprilysin, endothelin-converting enzyme 1 and 2, angiotensin-converting enzyme, and transthyretin, both in primary neuron cultures and female rat brains. Our results show that E2 and P4 affect the expression levels of several Aβ clearance factors in dose- and time-dependent manners. Most notably, expression of insulin-degrading enzyme is significantly increased by both hormones in cultured neurons and in vivo and is inversely associated with the soluble Aβ levels in vivo. These findings further define sex steroid hormone actions involved in regulation of Aβ, a relationship potentially important to therapeutic approaches aimed at reducing risk of Alzheimer's disease.

scholarly journals Immunohistochemical evidence of ubiquitous distribution of the metalloendoprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cell lines

2008 ◽  
Vol 389 (11) ◽  
Author(s):  
Gregor Weirich ◽  
Karin Mengele ◽  
Christina Yfanti ◽  
Apostolos Gkazepis ◽  
Daniela Hellmann ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Striated Muscle ◽  
Tumor Cell Lines ◽  
Trophoblast Cells ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
A Cell ◽  
Organ Tissue ◽  
Immunohistochemical Evidence

Abstract Immunohistochemical evidence of ubiquitous distribution of the metalloprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cells is presented. Immunohistochemical staining was performed on a multi-organ tissue microarray (pancreas, lung, kidney, central/peripheral nervous system, liver, breast, placenta, myocardium, striated muscle, bone marrow, thymus, and spleen) and on a cell microarray of 31 tumor cell lines of different origin, as well as trophoblast cells and normal blood lymphocytes and granulocytes. IDE protein was expressed in all the tissues assessed and all the tumor cell lines except for Raji and HL-60. Trophoblast cells and granulocytes, but not normal lymphocytes, were also IDE-positive.

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