Insulin-degrading enzyme (IDE) is a cytosolic zinc metallopeptidase that metabolizes several crucial bioactive peptides including insulin, the amyloid beta peptide (Ab), glucagon, and IGF-2. IDE is implicated in a poorly understood association between AD and type 2 diabetes (T2DM), and is consequently a target for developing novel therapeutic modalities for Alzheimer’s diseases (AD) and diabetes. We have recently established that IDE accumulates in the endocytic compartments (ERC) of the recycling endosome, contrary to the existing model of its activity within the endosomal system. Based on these observations, we hypothesized that IDE encounters its substrates specifically within the ERC. Our goal is to expand on this original discovery and understand the importance of this IDE pool in metabolizing Ab and insulin substrates as well as, more broadly, in cellular physiology. To this end, we examined the colocalization of IDE (hIDE<sup>wt</sup>-mApple) with an array of endosomal markers (Rab5, Rab7, Rab11, EHD1, EHD3) in IDE-KO Hela cells and found that IDE colocalizes with the recycling endosomal marker EHD1-GFP (Fig 1). Additionally, we mapped the overall endosomal distribution of labelled insulin and Ab (Insulin-Alexa488, Ab-Alexa488) in cells that also express IDE and found significant colocalization within the ERC. These key findings raise the previously unrecognized possibility that IDE interacts with Ab and insulin in the ERC, either in parallel with or instead of in the endolysosomal system, as has been postulated in the past.

Insulin-degrading enzyme: Distribution in recycling endosome key to degradation of insulin and amyloid beta

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