# Ubiquitin-Dependent Protein Regulation and Quality Control of the Lysosomal Membrane

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $327,600

## Abstract

Project Summary
The lysosome is an essential organelle responsible for the digestion and recycling of materials
delivered by endocytosis and autophagy. It also plays important roles in nutrient sensing and
control of cell growth by regulating the localization and activity of mTORC1 signaling complex.
Because of its importance, lysosome dysfunction leads to ~ 50 types of lysosomal storage
diseases (LSDs) and contributes to many aging-related neurodegenerative diseases such as
Alzheimer's, Huntington's, and Parkinson's diseases. Despite exhaustive research on how
proteins are delivered to lysosomes, how lysosomes regulate their own membrane proteins
remains poorly understood. However, studying this question will reveal how cells maintain a
healthy lysosome during stresses and aging.
Our long-term goal is to understand these fundamental questions using both yeast and
mammalian cells as model systems. Recently, we discovered a ubiquitin- and ESCRT-
dependent down-regulation pathway for lysosome (vacuole) membrane proteins in yeast.
Follow-up investigations in our laboratory led us to hypothesize that the ubiquitin- and ESCRT-
dependent degradation pathway is a general conserved mechanism to regulate the
lysosome membrane composition from yeast to human. Consistently, recent proteomic
studies identified multiple E3 ubiquitin ligases on the human lysosome membrane. Furthermore,
the ESCRT machinery was shown to be recruited to the human lysosome membrane.
In this proposed research, we plan to expand our initial findings by pursuing three specific aims.
Our Aim 1 will investigate how TORC1 regulates the vacuole membrane proteome via the
ubiquitin- and ESCRT-dependent pathway in yeast. Our Aim 2 will study how yeast vacuole
membrane E3 ligases recognize their membrane substrates at both structure and function level.
Our Aim 3 will study how human lysosomes turnover their membrane proteins. Our research
will shed light on the development of new treatment strategies for LSDs and lysosome-related
neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10246417
- **Project number:** 5R01GM133873-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ming Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $327,600
- **Award type:** 5
- **Project period:** 2019-09-13 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246417

## Citation

> US National Institutes of Health, RePORTER application 10246417, Ubiquitin-Dependent Protein Regulation and Quality Control of the Lysosomal Membrane (5R01GM133873-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246417. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*