Alternative titles; symbols
HGNC Approved Gene Symbol: IDE
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38): 10:92,451,684-92,574,093 (from NCBI)
Insulin-degrading enzyme (EC 3.4.24.56), also known as insulysin, is a 110-kD neutral metallopeptidase that can degrade a number of peptides, including insulin (176730) and beta-amyloid (104760) (Qiu et al., 1998).
Affholter et al. (1988) isolated and sequenced a cDNA coding for IDE. The deduced amino acid sequence of the enzyme contained the sequences of 13 peptides derived from the isolated protein. The cDNA transcribed in vitro yielded a synthetic RNA that in cell-free translations produced a protein that coelectrophoresed with the native proteinase and could be immunoprecipitated with monoclonal antibodies to IDE. Since the deduced sequence of this proteinase did not contain the consensus sequences for any of the known classes of proteinases (i.e., metallo, cysteine, aspartic, or serine), it may be a member of a family of proteases that are involved in intercellular peptide signaling. It did show homology to an Escherichia coli proteinase (called protease III), which also cleaves insulin and is present in the periplasmic space; thus, they may be members of the same family of proteases.
Qiu et al. (1998) determined that the extracellular thiol metalloprotease capable of degrading amyloid-beta protein identified by Qiu et al. (1997) is the same as IDE. By Western blot analysis, they found a full-length 110-kD IDE band in the CSF of normal individuals and of patients with Alzheimer disease (AD; 104300) or non-Alzheimer dementia. They found no difference in IDE levels of the normal and patient populations. By biochemical analysis of IDE purified from the medium of a mouse microglial cell line, they determined that IDE could degrade both endogenous and synthetic amyloid-beta protein and that it could catalyze the oligomerization of this protein.
Through a series of inhibitor studies, in vitro translation, and biochemical assays of rat IDE expressed by transfected human kidney cells, Edbauer et al. (2002) determined that IDE may be the protease responsible for the clearance of the cytoplasmic fragment of the amyloid-beta precursor protein (APP) following liberation of the amyloid-beta protein.
IDE has a preferential affinity for insulin such that the presence of insulin will inhibit IDE-mediated degradation of other substances, including beta-amyloid. Cook et al. (2003) found that hippocampal IDE levels were reduced by approximately 50% in AD patients with the APOE4 (107741) allele compared to AD patients without the APOE4 allele and to controls with or without the APOE4 allele. The findings suggested that reduced IDE expression may be a risk factor for AD, and that IDE may interact with APOE status to affect beta-amyloid metabolism.
Varicella-zoster virus (VZV) causes chickenpox and shingles. While varicella is likely spread as cell-free virus to susceptible hosts, the virus is transmitted by cell-to-cell spread in the body and in vitro. Li et al. (2006) found that the extracellular domain of IDE interacted with VZV glycoprotein E (gE), a protein essential for viral infection. Downregulation of IDE by small interfering RNA or blocking IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection. Cell-to-cell spread of virus was also impaired by blocking IDE. Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus. Li et al. (2006) concluded that IDE is a cellular receptor for both cell-free and cell-associated VZV.
Maianti et al. (2014) reported the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An x-ray structure of the macrocycle bound to IDE revealed that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor showed that IDE regulates the abundance and signaling of glucagon and amylin, in addition to that of insulin. Under physiologic conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. Maianti et al. (2014) concluded that these findings demonstrated the feasibility of modulating IDE activity as a therapeutic strategy to treat type II diabetes (see 125853), and expanded understanding of the roles of IDE in glucose and hormone regulation.
Affholter et al. (1990) mapped the IDE gene to human chromosome 10 and mouse chromosome 19 by hybridization of cDNA probes to human-rodent or mouse-hamster somatic cell hybrids, respectively. By a combination of somatic cell hybrid analysis and in situ hybridization, Espinosa et al. (1991) localized the IDE gene to 10q23-q25.
Crystal Structure
Shen et al. (2006) reported the crystal structure of human IDE in complex with 4 substrates, the insulin B chain (see 176730), amyloid beta(1-40), amylin (147940), and glucagon (138030). The amino- and carboxy-terminal domains of IDE form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between these domains keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form beta-sheets with 2 discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between the amino- and carboxy-termini of IDE increase IDE catalytic activity 40-fold.
For discussion of a possible association between variation in the IDE gene and late-onset Alzheimer disease, see AD6 (605526), which maps to chromosome 10q23-q25.
Abraham et al. (2001) analyzed all of the coding exons, untranslated regions, and 1,000 bp of 5-prime flanking sequence of IDE by means of denaturing HPLC and sequencing. They detected 8 single nucleotide polymorphisms (SNPs), of which 3 were found at lower than 5% frequency. None of them changed the amino acid sequence. Abraham et al. (2001) found no significant association between any individual SNP and late-onset AD (LOAD) or with any haplotypes. They concluded that IDE does not make a substantial contribution to the etiology of late-onset AD and therefore cannot account for the linkage between late-onset AD and 10q.
Prince et al. (2003) used a SNP genetic association strategy to investigate AD in relation to a 480-kb region encompassing IDE. They interpreted the results as providing 'substantial' evidence that genetic variation within or very close to IDE impacts both disease risk and traits related to the severity of AD.
Risk for LOAD and plasma amyloid-beta levels (APP; 104760), an intermediate phenotype for LOAD, show linkage to chromosome 10q. Ertekin-Taner et al. (2004) reported pathogenic variants in the 276-kb region of 10q harboring the IDE gene that influence intermediate DNA phenotypes and risk for AD.
Bian et al. (2004) reported an association between a T/C polymorphism (rs4646953) in the 5-prime untranslated region of the IDE gene, and AD in Han Chinese patients with the APOE4 allele. They found no association between several IDE polymorphisms and AD among patients without the E4 allele.
Genetic analysis of the diabetic GK rat has revealed several diabetes susceptibility loci (see 125853). Fakhrai-Rad et al. (2000) mapped one such locus, NIDDM1B, to a 1-cM region by genetic and pathophysiologic characterization of new congenic substrains for the locus. The IDE gene was also mapped to this 1-cM region, and 2 amino acid substitutions (H18R and A890V) were identified in the GK allele which reduced insulin-degrading activity by 31% in transfected cells. However, when the H18R and A890V variants were studied separately, no effects were observed, suggesting a synergistic effect of the 2 variants on insulin degradation. No effect on insulin degradation was observed in cell lysates, suggesting that the effect may be coupled to receptor-mediated internalization of insulin. Congenic rats with the IDE GK allele displayed postprandial hyperglycemia, reduced lipogenesis in fat cells, blunted insulin-stimulated glucose transmembrane uptake, and reduced insulin degradation in isolated muscle. Analysis of additional rat strains demonstrated that the dysfunctional IDE allele was unique to GK rats. The authors concluded that IDE plays an important role in the diabetic phenotype in GK rats.
Factors that elevate amyloid-beta (104760) peptide levels are associated with an increased risk for Alzheimer disease. Insulysin is one of several proteases potentially involved in degradation of amyloid-beta, based on its hydrolysis of amyloid-beta peptides in vitro. In an insulysin-deficient gene-trap mouse model, Miller et al. (2003) found that in vivo levels of brain A-beta-40 and A-beta-42 peptides were increased significantly. A 6-fold increase in the level of the gamma-secretase-generated C-terminal fragment of the A-beta precursor protein also was found in the insulysin-deficient mouse. In mice heterozygous for the insulysin gene trap, in which insulysin activity levels were decreased approximately 50%, brain A-beta peptides were increased to levels intermediate between those in wildtype mice and homozygous insulysin gene-trap mice that had no detectable insulysin activity. These findings indicated that there is an inverse correlation between in vivo insulysin activity levels and brain A-beta peptide levels and suggested that modulation of insulysin activity may alter the risk for Alzheimer disease.
Farris et al. (2003) generated mice deficient in IDE by targeted disruption. Ide deficiency resulted in a greater than 50% decrease in amyloid-beta degradation in both membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The Ide-null mice showed increased cerebral accumulation of endogenous amyloid-beta, a hallmark of Alzheimer disease, and had hyperinsulinemia and glucose intolerance (see 176730), hallmarks of type II diabetes. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which had recently been found to be degraded by IDE in vitro. Farris et al. (2003) concluded that, together with emerging genetic evidence, their in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of Alzheimer disease and type II diabetes and provide a mechanism for the recognized association among hyperinsulinemia, diabetes, and Alzheimer disease.
Leissring et al. (2003) found that developmentally delayed, neuron-specific overexpression of Ide or neprilysin (MME; 120520) in mice significantly reduced brain beta-amyloid levels, retarded or prevented amyloid plaque formation and its associated cytopathology, and rescued the premature lethality in APP transgenic mice. They concluded that chronic upregulation of beta-amyloid-degrading proteases may combat Alzheimer-type pathology in vivo.
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Cook, D. G., Leverenz, J. B., McMillan, P. J., Kulstad, J. J., Ericksen, S., Roth, R. A., Schellenberg, G. D., Jin, L.-W., Kovacina, K. S., Craft, S. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon-4 allele. Am. J. Path. 162: 313-319, 2003. [PubMed: 12507914] [Full Text: https://doi.org/10.1016/s0002-9440(10)63822-9]
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Ertekin-Taner, N., Allen, M., Fadale, D., Scanlin, L., Younkin, L., Petersen, R. C., Graff-Radford, N., Younkin, S. G. Genetic variants in a haplotype block spanning IDE are significantly associated with plasma A-beta-42 levels and risk for Alzheimer disease. Hum. Mutat. 23: 334-342, 2004. [PubMed: 15024728] [Full Text: https://doi.org/10.1002/humu.20016]
Espinosa, R., III, Lemons, R. S., Perlman, R. K., Kuo, W.-L., Rosner, M. R., Le Beau, M. M. Localization of the gene encoding insulin-degrading enzyme to human chromosome 10, bands q23-q25. Cytogenet. Cell Genet. 57: 184-186, 1991. [PubMed: 1743072] [Full Text: https://doi.org/10.1159/000133142]
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Maianti, J. P., McFedries, A., Foda, Z. H., Kleiner, R. E., Du, X. Q., Leissring, M. A., Tang, W.-J., Charron, M. J., Seeliger, M. A., Saghatelian, A., Liu, D. R. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature 511: 94-98, 2014. [PubMed: 24847884] [Full Text: https://doi.org/10.1038/nature13297]
Miller, B. C., Eckman, E. A., Sambamurti, K., Dobbs, N., Chow, K. M., Eckman, C. B., Hersh, L. B., Thiele, D. L. Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc. Nat. Acad. Sci. 100: 6221-6226, 2003. [PubMed: 12732730] [Full Text: https://doi.org/10.1073/pnas.1031520100]
Prince, J. A., Feuk, L., Gu, H. F., Johansson, B., Gatz, M., Blennow, K., Brookes, A. J. Genetic variation in a haplotype block spanning IDE influences Alzheimer disease. Hum. Mutat. 22: 363-371, 2003. [PubMed: 14517947] [Full Text: https://doi.org/10.1002/humu.10282]
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