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Article

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

1
Instituto de Biología y Genética Molecular, Excellence Unit, University of Valladolid-CSIC, 47003 Valladolid, Spain
2
Instituto de Neurociencias de Castilla y León (INCYL), University of Salamanca, 37007 Salamanca, Spain
3
Hospital Virgen de la Vega-Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
4
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Thierry Coppola
Cells 2022, 11(2), 227; https://doi.org/10.3390/cells11020227
Received: 14 December 2021 / Revised: 29 December 2021 / Accepted: 31 December 2021 / Published: 11 January 2022
(This article belongs to the Special Issue Insulin-Degrading Enzyme in Health and Disease)
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. View Full-Text
Keywords: insulin-degrading enzyme; phylogeny; molecular evolution; intron-exon structure; microglia; lipid rafts; extracellular vesicles; inflammatory state; amyloid β; oxidative stress insulin-degrading enzyme; phylogeny; molecular evolution; intron-exon structure; microglia; lipid rafts; extracellular vesicles; inflammatory state; amyloid β; oxidative stress
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MDPI and ACS Style

Corraliza-Gómez, M.; Lillo, C.; Cózar-Castellano, I.; Arranz, E.; Sanchez, D.; Ganfornina, M.D. Evolutionary Origin of Insulin-Degrading Enzyme and Its Subcellular Localization and Secretion Mechanism: A Study in Microglial Cells. Cells 2022, 11, 227. https://doi.org/10.3390/cells11020227

AMA Style

Corraliza-Gómez M, Lillo C, Cózar-Castellano I, Arranz E, Sanchez D, Ganfornina MD. Evolutionary Origin of Insulin-Degrading Enzyme and Its Subcellular Localization and Secretion Mechanism: A Study in Microglial Cells. Cells. 2022; 11(2):227. https://doi.org/10.3390/cells11020227

Chicago/Turabian Style

Corraliza-Gómez, Miriam, Concepción Lillo, Irene Cózar-Castellano, Eduardo Arranz, Diego Sanchez, and Maria D. Ganfornina. 2022. "Evolutionary Origin of Insulin-Degrading Enzyme and Its Subcellular Localization and Secretion Mechanism: A Study in Microglial Cells" Cells 11, no. 2: 227. https://doi.org/10.3390/cells11020227

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