# Insulin Degrading Enzyme: Physiological Function and its Spatial and Activity Modulation

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $411,769

## Abstract

Insulin-degrading enzyme (IDE, insulysin) is a primarily cytosolic peptidase shown to be
important in the catabolism of insulin, the amyloid beta peptide, and likely other signaling and
intracellular peptides. Its cellular physiology is therefore of considerable interest in the treatment
of disorders such as diabetes and Alzheimer's disease. However the site of IDE action on these
peptides, which are internalized into or otherwise present in the endosomal system, is yet to be
fully understood. We propose to address the question of how this cytosolic enzyme encounters
substrate peptides, like insulin, in the endosomal system, exploring a novel mechanism for IDE
subcellular localization to this compartment. In particular, we propose that IDE is trafficked to
endosomes by binding to membrane anionic lipids, particularly phosphoinositides, through a
polyanion-binding site. In the first aim, we will test this hypothesis by using IDE polyanion site
mutants, by altering levels of a key phosphoinositide, and by expressing a phosphoinositide
binding competitor. We further propose to study, in the second aim, the participation of
endosomal IDE in insulin and amyloid(beta(peptide(catabolism. We will manipulate endosomal
IDE levels using mutant forms of the enzyme with reduced endosome localization, by
decreasing PtdIns(3)P levels, and by increasing endosomal IDE by fusing it with a PtdIns(3)P-
targeting domain. In the third aim, we will study the polyanion-dependent activation of IDE and
its role in affecting its catabolism of cytosolic peptides. We will use IDE mutants to test the effect
of activation on hydrolysis of peptide substrates identified using a ligand trapping technique and
peptidomic analyses. We will also test for activation of cellular IDE by inositol phosphates and
other potential endogenous activators. We will use our trapping technique to identify other
endogenous effectors. These studies will develop a clearer picture of how IDE carries out its
physiological functions and greatly benefit efforts to treat IDE related pathophysiological states.(

## Key facts

- **NIH application ID:** 9989878
- **Project number:** 5R01GM130954-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Louis Hersh Louis Hersh Louis Hersh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,769
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989878

## Citation

> US National Institutes of Health, RePORTER application 9989878, Insulin Degrading Enzyme: Physiological Function and its Spatial and Activity Modulation (5R01GM130954-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9989878. Licensed CC0.

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