# ANALYSIS OF ESCRT FUNCTION IN ENDOLYSOSOMAL TRAFFICKING

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $395,888

## Abstract

The endolysosomal network is the portal by which extracellular material enters the cell. As such, the
membranes of the endosomes, phagosomes, and lysosomes that comprise this network face challenges from
pathogens and other internalized materials as well as from metabolic and chemical stresses. Consequences of
damage vary according to the specific compartment and degree of damage, but extensive lysosomal
membrane permeabilization triggers cell death while limited disruption of endosomes and phagosomes by
particulate material and pathogens leads to inflammasome activation and ensuing cytokine responses. A
widely deployed strategy for removing damaged organelles involves the use of selective autophagy, referred to
as lysophagy. Removal is, however, unnecessary if organelles are instead repaired. We recently discovered a
new role for the ESCRT (endosomal sorting complex required for transport) machinery in responding to nano-
scale disruptions in endolysosomal membranes and promoting their repair. In this proposal, we will build on
this discovery and test the hypothesis that ESCRTs (and in particular ESCRT-III proteins) act as a dynamic
membrane stabilizing system to protect vulnerable membranes across the endolysosomal network and
beyond. Two aims will exploit and explore responses to two experimentally tractable and sterile endolysosomal
disruptants that potently engage the ESCRT machinery. In Aim 1, we will determine how the ESCRT
machinery recognizes and counteracts lysosomal membrane stress induced by L-leucyl-L-leucine methyl ester
(LLOMe). This will involve characterizing the membrane stress responsible for engaging ESCRTs, defining the
molecular pathway(s) involved and identifying “keystone” ESCRT-III proteins, delineating the molecular
features required for repair, and identifying pathways that trigger this stabilizing response. In Aim 2, we will
examine how ESCRTs respond to and repair silica induced membrane damage in epithelial and phagocytic
cells. This will include testing a role for Fe2+-dependent lipid peroxidation in engaging ESCRTs, imaging the
relative role and dynamics of ESCRT components on phagosomal membranes, and testing the hypothesis that
ESCRTs limit endolysosomal damage in phagocytic cells and thereby dampen inflammation associated with
the many things that transit through these pathways. The insights gained from this work will be applicable to
understanding how ESCRTs sense and respond to a broad range of membrane stresses.

## Key facts

- **NIH application ID:** 10914643
- **Project number:** 5R01GM122434-08
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Phyllis I Hanson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,888
- **Award type:** 5
- **Project period:** 2017-01-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914643

## Citation

> US National Institutes of Health, RePORTER application 10914643, ANALYSIS OF ESCRT FUNCTION IN ENDOLYSOSOMAL TRAFFICKING (5R01GM122434-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10914643. Licensed CC0.

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